Bis(difluoromethyl)pyrazoles as Fungicides

ABSTRACT

Bis(difluoromethyl)pyrazole derivatives of the formula (I) 
     
       
         
         
             
             
         
       
     
     in which the symbols R 1 , X and G are each as defined in the description, and agrochemically active salts, metal complexes and N-oxides thereof, and use thereof for controlling phytopathogenic harmful fungi, and also processes for preparing compounds of the formula (I).

The invention relates to bis(difluoromethyl)pyrazole derivatives, toagrochemically active salts thereof, to use thereof and to methods andcompositions for controlling phytopathogenic harmful fungi in and/or onplants or in and/or on seed of plants, to processes for producing suchcompositions and treated seed, and to use thereof for controllingphytopathogenic harmful fungi in agriculture, horticulture and forestry,in animal health, in the protection of materials and in the domestic andhygiene sector. The present invention further relates to a process forpreparing bis(difluoromethyl)pyrazole derivatives.

It is already known that particular substituted pyrazole derivatives canbe used as fungicidal crop protection compositions (see WO 07/014290, WO08/013925, WO 08/013622, WO 08/091594, WO 08/091580, WO 09/055514, WO09/094407, WO 09/094445, WO 09/132785, WO 10/037479, WO 10/065579, WO10/066353, WO 10/123791; see also patent applications with applicationnumbers: DE102010000662.9, PCT/EP2010/003499, EP09174510.9,EP09174614.9; EP09180073.0, EP10161264.6, EP10163067.1, EP10164099.3,EP10172486.2, EP10174012.4, EP10189067.1). However, specifically atrelatively low application rates, the fungicidal activity of thesecompounds is not always sufficient.

Since the ecological and economic demands made on modern crop protectioncompositions are increasing constantly, for example with respect toactivity spectrum, toxicity, selectivity, application rate, formation ofresidues and favourable manufacture, and problems with resistances, forexample, can also occur, there is a constant need to develop novel cropprotection compositions, especially fungicides, which, at least in someareas, have advantages over the known ones.

It has now been found that, surprisingly, the presentbis(difluoromethyl)pyrazole derivatives achieve at least some aspects ofthe objects mentioned and are suitable for use as crop protectioncompositions, especially as fungicides.

The invention relates to compounds of the formula (I)

in which the symbols are each defined as follows:

-   X is oxygen or sulphur,-   G is

-   R¹ is hydrogen or halogen,-   R² is C₁-C₆-alkyl or C₁-C₆-haloalkyl,-   or-   R² is a C₃-C₈-cycloalkyl which may contain up to two substituents,    where the substituents are each independently selected from the    following list:    -   cyano, halogen, hydroxyl oxo, C₁-C₄-alkyl, C₁-C₄-haloalkyl,        C₁-C₄-alkoxy, C₁-C₄-haloalkoxy, C₁-C₄-alkylthio,        C₁-C₄-haloalkylthio or phenyl,-   or-   R² is a C₅-C₈-cycloalkenyl which may contain up to two substituents,    where the substituents are each independently selected from the    following list:    -   cyano, halogen, hydroxyl, oxo, C₁-C₄-alkyl, C₁-C₄-haloalkyl,        C₁-C₄-haloalkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy,        C₁-C₄-alkylthio, C₁-C₄-haloalkylthio or phenyl,-   or-   R² is a phenyl which may contain up to two substituents, where the    substituents are each independently selected from the following    list:    -   amino, halogen, cyano, hydroxyl, SH, nitro, C(═O)H, C₁-C₆-alkyl,        C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₁-C₆-haloalkyl,        C₂-C₆-haloalkenyl, C₂-C₆-haloalkynyl, C₃-C₈-cycloalkyl,        C₃-C₈-halocycloalkyl, C₄-C₁₀-alkylcycloalkyl,        C₄-C₁₀-cycloalkylalkyl, C₆-C₁₄-cycloalkylcycloalkyl,        C₄-C₁₀-halocycloalkylalkyl, C₅-C₁₀-alkylcycloalkylalkyl,        C₃-C₈-cycloalkenyl, C₃-C₈-halocycloalkenyl, C₂-C₆-alkoxyalkyl,        C₄-C₁₀-cycloalkoxyalkyl, C₃-C₈-alkoxyalkoxyalkyl,        C₂-C₆-alkylthioalkyl, C₂-C₆-alkylsulphinylalkyl,        C₂-C₆-alkylsulphonylalkyl, C₂-C₆-alkylaminoalkyl,        C₃-C₈-dialkylaminoalkyl, C₂-C₆-haloalkylaminoalkyl,        C₄-C₁₀-cycloalkylaminoalkyl, C₂-C₆-alkylcarbonyl,        C₂-C₆-haloalkylcarbonyl, C₄-C₈-cycloalkylcarbonyl,        C₂-C₆-alkoxycarbonyl, C₄-C₈-cycloalkoxycarbonyl,        C₅-C₁₀-cycloalkylalkoxycarbonyl, C₂-C₆-alkylaminocarbonyl,        C₃-C₈-dialkylaminocarbonyl, C₄-C₈-cycloalkylaminocarbonyl,        C₂-C₆-haloalkoxyalkyl, C₁-C₆-hydroxyalkyl, C₃-C₆-alkoxy,        C₁-C₆-haloalkoxy, C₃-C₈-cycloalkoxy, C₃-C₈-halocycloalkoxy,        C₄-C₁₀-cycloalkylalkoxy, C₂-C₆-alkenyloxy, C₂-C₆-haloalkenyloxy,        C₂-C₆-alkynyloxy, C₂-C₆-haloalkynyloxy, C₂-C₆-alkoxyalkoxy,        C₂-C₆-alkylcarbonyloxy, C₂-C₆-haloalkylcarbonyloxy,        C₄-C₈-cycloalkylcarbonyloxy, C₃-C₆-alkylcarbonylalkoxy,        C₁-C₆-alkylthio, C₁-C₆-haloalkylthio, C₃-C₆-cycloalkylthio,        C₁-C₆-alkylsulphinyl, C₁-C₆-haloalkylsulphinyl,        C₁-C₆-alkylsulphonyl, C₁-C₆-haloalkylsulphonyl,        C₃-C₆-cycloalkylsulphonyl, tri(C₁-C₄-alkyl)silyl,        C₁-C₆-alkylsulphonylamino, C₁-C₆-haloalkylsulphonylamino or -LQ,-   or-   R² is naphthyl, dihydronaphthalenyl, tetrahydronaphthalenyl,    hexahydronaphthalenyl, octahydronaphthalenyl or indenyl which may    contain up to two substituents, where the substituents are each    independently selected from the following list:    -   cyano, nitro, halogen, C₁-C₆-alkyl, C₁-C₄-haloalkyl,        C₃-C₆-cycloalkyl, C₂-C₆-alkenyl, C₂-C₆-haloalkenyl,        C₂-C₆-alkynyl, C₂-C₆-haloalkynyl, tri(C₁-C₄-alkyl)silyl, benzyl,        phenyl, hydroxyl, SH, oxo, C₁-C₆-alkoxy, C₁-C₆-haloalkoxy,        C₂-C₆-alkenyloxy, C₂-C₆-alkynyloxy, C₁-C₆-alkylthio or        C₁-C₆-haloalkylthio,-   or-   R² is a 5- or 6-membered heteroaryl radical which may contain up to    two substituents, where the substituents are each independently    selected from the following list:    -   substituents on carbon: halogen, cyano, nitro, hydroxyl, SH,        C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₁-C₆-haloalkyl,        C₂-C₆-haloalkenyl, C₂-C₆-haloalkynyl, C₃-C₆-cycloalkyl,        C₃-C₆-halocycloalkyl, C₄-C₁₀-alkylcycloalkyl,        C₄-C₁₀-cycloalkylalkyl, C₆-C₁₄-cycloalkylcycloalkyl,        C₅-C₁₀-alkylcycloalkylalkyl, C₂-C₄-alkoxyalkyl,        C₂-C₄-alkylcarbonyl, C₂-C₆-alkoxycarbonyl,        C₂-C₆-alkylaminocarbonyl, C₃-C₈-dialkylaminocarbonyl,        C₁-C₄-hydroxyalkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy,        C₂-C₆-alkylcarbonyloxy, C₂-C₆-alkylcarbonylthio,        C₁-C₄-alkylthio, C₁-C₄-haloalkylthio, C₁-C₄-alkylsulphinyl,        C₁-C₄-haloalkylsulphinyl, C₁-C₄-alkylsulphonyl,        C₁-C₄-haloalkylsulphonyl, tri(C₁-C₄-alkyl)silyl or -LQ,    -   substituents on nitrogen: C₁-C₆-alkyl, C₂-C₆-alkenyl,        C₂-C₆-alkynyl, C₁-C₆-haloalkyl, C₂-C₆-haloalkenyl,        C₂-C₆-haloalkynyl, C₃-C₆-cycloalkyl, C₃-C₆-halocycloalkyl,        C₄-C₁₀-alkylcycloalkyl, C₄-C₁₀-cycloalkylalkyl,        C₁-C₄-alkylsulphonyl, C(═O)H, C(═O)Me, C(═O)OMe, benzyl or        phenyl,-   or-   R² and R³, together with the carbon atom to which they are bonded,    form a 5- to 12-membered unsubstituted or substituted, partly    saturated or unsaturated, mono- or bicyclic ring system which may    contain up to three further heteroatoms selected from N, O and S,    where no two oxygen atoms are adjacent and where any possible    substituents are selected independently from halogen. C₁-C₄-alkyl,    C₁-C₄-haloalkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy, oxo, hydroxyl,    benzyl and phenyl,-   R³ is hydrogen, cyano, C₁-C₃-alkyl or C₁-C₃-haloalkyl,-   R^(Tz) is halogen or hydrogen-   L is a direct bond, —CH₂—, —(C═O)—, sulphur or oxygen.-   Q is a phenyl which may contain up to two substituents, where the    substituents are each independently selected from the following    list:    -   halogen, cyano, nitro, hydroxyl, SH, C₁-C₆-alkyl, C₂-C₆-alkenyl,        C₂-C₆-alkynyl, C₁-C₆-haloalkyl, C₂-C₆-haloalkenyl,        C₂-C₆-haloalkynyl, C₃-C₈-cycloalkyl, C₃-C₈-halocycloalkyl,        C₂-C₆-alkoxyalkyl, C₂-C₆-alkylcarbonyl, C₂-C₆-haloalkylcarbonyl,        C₂-C₆-alkoxycarbonyl, C₁-C₆-alkoxy, C₁-C₆-haloalkoxy,        C₃-C₈-cycloalkoxy, C₃-C₈-halocycloalkoxy, C₂-C₆-alkenyloxy,        C₂-C₆-alkynyloxy, C₂-C₆-alkoxyalkoxy, C₁-C₆-alkylthio,        C₁-C₆-haloalkylthio, C₁-C₆-alkylsulphinyl,        C₁-C₆-haloalkylsulphinyl, C₁-C₆-alkylsulphonyl,        C₁-C₆-haloalkylsulphonyl, tri(C₁-C₄-alkyl)silyl or phenyl,-   or-   Q is a 5- or 6-membered heteroaryl radical which may contain up to    two substituents, where the substituents are each independently    selected from the following list:    -   substituents on carbon: halogen, cyano, nitro, hydroxyl, SH,        C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₁-C₆-haloalkyl,        C₂-C₆-haloalkenyl, C₂-C₆-haloalkyl, C₂-C₆-haloalkynyl,        C₃-C₆-cycloalkyl, C₃-C₆-halocycloalkyl, C₄-C₁₀-alkylcycloalkyl,        C₄-C₁₀-cycloalkylalkyl, C₆-C₁₄-cycloalkylcycloalkyl,        C₅-C₁₀-alkylcycloalkylalkyl, C₂-C₄-alkoxyalkyl,        C₂-C₄-alkylcarbonyl, C₂-C₆-alkoxycarbonyl. C₁-C₄-alkoxy,        C₁-C₄-haloalkoxy, C₂-C₆-alkylcarbonyloxy,        C₂-C₆-alkylcarbonylthio, C₁-C₄-alkylthio, C₁-C₄-haloalkylthio,        C₁-C₄-alkylsulphinyl, C₁-C₄-haloalkylsulphinyl,        C₁-C₄-alkylsulphonyl, C₁-C₄-haloalkylsulphonyl,        tri(C₁-C₄-alkyl)silyl or phenyl,    -   substituents on nitrogen: C₁-C₄-alkyl, C₂-C₄-alkenyl,        C₂-C₄-alkynyl, C₁-C₄-haloalkyl, C₂-C₄-haloalkenyl,        C₂-C₄-haloalkynyl, C₃-C₆-cycloalkyl, C₁-C₄-alkylsulphonyl,        C(═O)H, C(═O)Me, C(═O)OMe or phenyl,-   and agrochemically active salts, metal complexes and N-oxides    thereof.

The invention further provides for the use of the compounds of theformula (I) as a fungicide.

Inventive bis(difluoromethyl)pyrazole derivatives of the formula (I) andthe agrochemically active salts, metal complexes and N-oxides thereofare very suitable for controlling phytopathogenic harmful fungi. Theaforementioned inventive compounds exhibit potent fungicidal activity inparticular, and can be used in crop protection, in the domestic andhygiene sector, and in the protection of materials.

The compounds of the formula (I) may be present either in pure form oras mixtures of different possible isomeric forms, especially ofstereoisomers, such as E and Z, threo and erythro, and also opticalisomers, such as R and S isomers or atropisomers, and, if appropriate,also of tautomers. Both the E and the Z isomers are claimed, as are thethreo and erythro isomers, and also the optical isomers, all possiblemixtures of these isomers, and also the possible tautomeric forms.

The bis(difluoromethyl)pyrazole derivatives usable in accordance withthe invention are defined in general terms by the formula (I). Preferredradical definitions for the above formula shown and those specifiedbelow are specified hereinafler. These definitions apply equally to theend products of the formula (I) and to all intermediates (see also belowunder “Illustrations of the processes and intermediates”).

-   X is preferably oxygen,-   R¹ is preferably hydrogen or fluorine,-   G is preferably G1, G3 and G4,-   G is more preferably

-   R² is preferably a C₃-C₈-cycloalkyl which may contain up to two    substituents, where the substituents are each independently selected    from the following list:    -   cyano, halogen, hydroxyl, oxo, C₁-C₄-alkyl, C₁-C₄-haloalkyl,        C₁-C₄-alkoxy, C₁-C₄-haloalkoxy, C₁-C₄-alkylthio,        C₁-C₄-haloalkylthio or phenyl,-   R² is also preferably a phenyl which may contain up to two    substituents, where the substituents are each independently selected    from the following list:    -   amino, halogen, cyano, hydroxyl, SH, nitro, C(═O)H, C₁-C₆-alkyl,        C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₁-C₆-haloalkyl,        C₂-C₆-haloalkenyl, C₂-C₆-haloalkynyl, C₃-C₈-cycloalkyl,        C₃-C₈-halocycloalkyl, C₄-C₁₀-alkylcycloalkyl,        C₄-C₁₀-cycloalkylalkyl, C₆-C₁₄-cycloalkylcycloalkyl,        C₄-C₁₀-halocycloalkylalkyl, C₅-C₁₀-alkylcycloalkylalkyl,        C₃-C₈-cycloalkenyl, C₃-C₈-halocycloalkenyl, C₂-C₆-alkoxyalkyl,        C₄-C₁₀-cycloalkoxyalkyl, C₃-C₈-alkoxyalkoxyalkyl,        C₂-C₆-alkylthioalkyl, C₂-C₆-alkylsulphinylalkyl,        C₂-C₆-alkylsulphonylalkyl, C₂-C₆-alkylaminoalkyl,        C₃-C₈-dialkylaminoalkyl, C₂-C₆-haloalkylaminoalkyl,        C₄-C₁₀-cycloalkylaminoalkyl, C₂-C₆-alkylcarbonyl,        C₂-C₆-haloalkylcarbonyl, C₄-C₈-cycloalkylcarbonyl,        C₂-C₆-alkoxycarbonyl, C₄-C₈-cycloalkoxycarbonyl,        C₅-C₁₀-cycloalkylalkoxycarbonyl, C₂-C₆-alkylaminocarbonyl,        C₃-C₈-dialkylaminocarbonyl, C₄-C₈-cycloalkylaminocarbonyl,        C₂-C₆-haloalkoxyalkyl, C₁-C₆-hydroxyalkyl, C₁-C₆-alkoxy,        C₁-C₆-haloalkoxy, C₃-C₈-cycloalkoxy, C₃-C₈-halocycloalkoxy,        C₄-C₁₀-cycloalkylalkoxy, C₂-C₆-alkenyloxy, C₂-C₆-haloalkenyloxy,        C₂-C₆-alkynyloxy, C₂-C₆-haloalkynyloxy, C₂-C₆-alkoxyalkoxy,        C₂-C₆-alkylcarbonyloxy, C₂-C₆-haloalkylcarbonyloxy,        C₄-C₈-cycloalkylcarbonyloxy, C₃-C₆-alkylcarbonylalkoxy,        C₁-C₆-alkylthio, C₁-C₆-haloalkylthio, C₃-C₆-cycloalkylthio,        C₁-C₆-alkylsulphinyl, C₁-C₆-haloalkylsulphinyl,        C₁-C₆-alkylsulphonyl, C₁-C₆-haloalkylsulphonyl,        C₃-C₈-cycloalkylsulphonyl, tri(C₁-C₄-alkyl)silyl,        C₁-C₆-alkylsulphonylamino, C₁-C₆-haloalkylsulphonylamino or -LQ.-   R² is also preferably a 5- or 6-membered heteroaryl radical which    may contain up to two substituents, where the substituents are each    independently selected from the following list:    -   substituents on carbon: halogen, cyano, nitro, hydroxyl, SH,        C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₁-C₆-haloalkyl,        C₂-C₆-haloalkenyl, C₂-C₆-haloalkynyl, C₃-C₆-cycloalkyl,        C₃-C₆-halocycloalkyl, C₄-C₁₀-alkylcycloalkyl,        C₄-C₁₀-cycloalkylalkyl, C₆-C₁₄-cycloalkylcycloalkyl,        C₅-C₁₀-alkylcycloalkylalkyl, C₂-C₄-alkoxyalkyl,        C₂-C₄-alkylcarbonyl, C₂-C₆-alkoxycarbonyl,        C₂-C₆-alkylaminocarbonyl, C₃-C₈-dialkylaminocarbonyl,        C₁-C₄-hydroxyalkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy,        C₂-C₆-alkylcarbonyloxy, C₂-C₆-alkylcarbonylthio,        C₁-C₄-alkylthio, C₁-C₄-haloalkylthio, C₁-C₄-alkylsulphonyl,        C₁-C₄-haloalkylsulphinyl, C₁-C₄-alkylsulphonyl,        C₁-C₄-haloalkylsulphonyl, tri(C₁-C₄-alkyl)silyl or -LQ,    -   substituents on nitrogen: C₁-C₆-alkyl, C₂-C₆-alkenyl,        C₂-C₆-alkynyl, C₁-C₆-haloalkyl, C₂-C₆-haloalkenyl,        C₂-C₆-haloalkynyl, C₃-C₆-cycloalkyl, C₃-C₆-halocycloalkyl,        C₄-C₁₀-alkylcycloalkyl, C₄-C₁₀-cycloalkylalkyl,        C₁-C₄-alkylsulphonyl, C(═O)H, C(═O)Me, C(═O)OMe, benzyl or        phenyl,-   R² is more preferably a phenyl which may contain up to two    substituents, where the substituents are each independently selected    from the following list:    -   amino, halogen, cyano, nitro, C₁-C₆-alkyl, C₂-C₆-alkenyl,        C₂-C₆-alkynyl, C₁-C₆-haloalkyl, C₂-C₆-haloalkenyl,        C₂-C₆-haloalkynyl, C₃-C₈-cycloalkyl, C₃-C₈-halocycloalkyl,        C₂-C₆-alkoxyalkyl, C₂-C₆-alkylcarbonyl, C₂-C₆-haloalkylcarbonyl,        C₂-C₆-alkoxycarbonyl, C₁-C₆-alkoxy, C₁-C₆-haloalkoxy,        C₃-C₈-cycloalkoxy, C₃-C₈-halocycloalkoxy, C₂-C₆-alkenyloxy,        C₂-C₆-alkynyloxy, C₂-C₆-alkoxyalkoxy, C₁-C₆-alkylthio,        C₁-C₆-haloalkylthio, C₁-C₆-alkylsulphinyl,        C₁-C₆-haloalkylsulphinyl, C₁-C₆-alkylsulphonyl,        C₁-C₆-haloalkylsulphonyl, or phenyl,-   R² is even more preferably a phenyl which may contain up to two    substituents, where the substituents are each independently selected    from the following list:    -   chlorine, fluorine, bromine, iodine, cyano, nitro, —CH₃,        —CH₂CH₃, —CH₂CH₂CH₃, —CH(CH₃)₂, —CH₂CH₂CH₂CH₃, —CH(CH₃)CH₂CH₃,        —CH₂CH(CH₃)CH₃, —C(CH₃)₃, —CH═CH₂. —CH═CHCH₃, —CH₂CH═CH₂,        —CH═CHCH₂CH₃, —CH₂CH═CHCH₃, —CH₂CH₃CH═CH₂, —C≡CH, —C≡CCH₃,        —CH₂C≡CH, —C≡CCH₂CH₃, —CH₂C≡CCH₃, —CH₂CH₂C≡CH, —CF₃, —CFH₂,        —CF₂H, —CF₂CF₃, —CCl₃, cyclopropyl, cyclobutyl, cyclopentyl,        cyclohexyl, —CH₂OCH₃, —CH₂OCH₂CH₃, —CH₂CH₂OCH₃, —CH₂OCH₂CH₂CH₃,        —CH₂CH₂OCH₂CH₃, —CH₂CH₂CH₂OCH₃, —C(═O)CH₃, —C(═O)CH₃CH₃.        C(═O)CH₂CH₂CH₃, C(═O)CH(CH₃)₂, —C(═O)CF₃, —C(═O)OCH₃,        —C(═O)OCH₂CH₃, —C(═O)OCH₂CH₂CH₃, —C(═O)OCH(CH₃)₂, —OCH₃,        —OCH₂CH₃, —OCH₂CH₂CH₃, —OCH(CH₃)₂, —OCH₂CH₂CH₂CH₃,        —OCH₂CH(CH₃)₂. —OCH(CH)CH₂CH₃, —OC(CH₃)₃, —OCF₃, —OCF₂H,        —OCH₂CF₃, —OCF₂CF₃, O-cyclohexyl, O-cyclopentyl, O-cyclopropyl,        —SCH₃, —SCH₂CH₃, —SCH₂CH₂CH₃, —SCH(CH₃)₂, —SCH₂CH₂CH₂CH₃,        —SCH₂CH(CH₃)₂, —SCH(CH₃)CH₂CH₃, —SC(CH₃)₃, —SCF₃, —SCF₂H.        —SCH₂CF₃, —SCF₂CF₃, —S(═O)Me, —S(O)CF₃, —S(═O)₂Me, —S(O)₂CF₃,        —OCH₂CHCH₂, —OCH₂C≡CH, —OCH₂OCH₃, —OCH₂OCH₂CH₃, —OCH₂CH₂OCH₃,        —OCH₂OCH(CH₃)₂, trimethylsilyl or phenyl,-   R² is especially preferably a phenyl which may contain up to two    substituents, where the substituents are each independently selected    from the following list:    -   fluorine, chlorine, bromine, —CH₃ or phenyl,-   R³ is preferably hydrogen, cyano or C₁-C₃-alkyl,-   R³ is more preferably hydrogen or methyl, ethyl, n-propyl,    isopropyl,-   R³ is even more preferably hydrogen,-   R^(Tz) is preferably chlorine or hydrogen and more preferably    hydrogen,-   L is preferably a direct bond or oxygen,-   Q is preferably a phenyl which may contain up to two substituents,    where the substituents are each independently selected from the    following list:    -   halogen, cyano, hydroxyl, nitro, SH, C₁-C₆-alkyl,        C₁-C₆-haloalkyl, C₃-C₆-cycloalkyl, C₁-C₄-alkoxy,        C₁-C₄-haloalkoxy, C₁-C₄-haloalkoxy, C₁-C₄-alkylthio,        C₁-C₄-haloalkylthio or phenyl,-   Q is also preferably a 5- or 6-membered heteroaryl radical which may    contain up to two substituents, where the substituents are each    independently selected from the following list:    -   substituents on carbon:    -   halogen, cyano, hydroxyl, nitro. SH, C₁-C₆-alkyl,        C₁-C₆-haloalkyl, C₃-C₆-cycloalkyl, C₁-C₄-alkoxy,        C₁-C₄-haloalkoxy, C₁-C₄-haloalkoxy, C₁-C₄-alkylthio,        C₁-C₄-haloalkylthio or phenyl,    -   substituents on nitrogen: C₁-C₆-alkyl, C₂-C₆-alkenyl,        C₂-C₆-alkynyl, C₃-C₆-cycloalkyl or phenyl,-   and agrochemically active salts, metal complexes and N-oxides    thereof.

The radical definitions and explanations given above in general terms orstated within preferred ranges can, however, also be combined with oneanother as desired, i.e. including between the particular ranges andpreferred ranges. They apply both to the end products andcorrespondingly to precursors and intermediates. Moreover, individualdefinitions may not apply.

Preference is given to compounds of the formula (I) in which allradicals in each case have the preferred definitions mentioned above.

Particular preference is given to compounds of the formula (I) in whichall radicals in each case have the more preferred definitions mentionedabove.

Very particular preference is given to compounds of the formula (I) inwhich all radicals in each case have the even more preferred definitionsmentioned above.

Special preference is given to compounds of the formula (I) in which allradicals in each case have the especially preferred definitionsmentioned above.

Preference is further given to compounds of the formula (I) in which

-   X is oxygen,-   G is G3 and/or G4 and is especially G3,-   R¹ is fluorine or hydrogen and is especially hydrogen,-   R¹ is phenyl, 2-fluorophenyl, 2,6-difluorophenyl, 2-acetylphenyl,    3-acetylphenyl, 2-hydroxyphenyl, 2-nitrophenyl,    2-[(2-methoxyethoxy)methyl]phenyl,    2-[(ethyl-sulphanyl)methyl]phenyl,    2-[(cyclopropylmethoxy)carbonyl]phenyl, 2-(allyloxy)phenyl,    3-(but-2-yn-1-yloxy)phenyl, 2-(butoxymethyl)phenyl,    2-fluoro-6-formylphenyl, 2-[(2-methylprop-2-en-1-yl)oxy]phenyl,    2-(2-methoxyethoxy)phenyl, 2-[(3-methylbut-2-en-1-yl)oxy]phenyl,    3-(prop-2-yn-1-yloxy)phenyl, 4-(prop-2-yn-1-yloxy)phenyl,    3-formylphenyl, 2-(cyclohexylmethoxy)phenyl,    2-(pent-2-yn-1-yloxy)phenyl, 2-formylphenyl,    2-(cyclopropylcarbamoyl)phenyl, 2-(but-2-yn-1-yloxy)-6-fluorophenyl,    2-fluoro-6-(prop-2-yn-1-yloxy)phenyl,    2-[(cyclohexylcarbonyl)oxy]phenyl,    2-[(cyclopropyl-carbonyl)oxy]phenyl, 3-(pent-2-yn-1-yloxy)phenyl,    2-(but-2-yn-1-yloxy)phenyl, 2-[(3,3,3-trifluoropropanoyl)oxy]phenyl,    2-[(methylsulphonyl)amino]phenyl, 2-ethynylphenyl,    2-(prop-2-yn-1-yloxy)phenyl, 4-[(methylsulphonyl)amino]phenyl,    2-aminophenyl, 3-hydroxyphenyl, 2-(methoxycarbonyl)phenyl,    2-(chloromethyl)phenyl, 4-(pent-2-yn-1-yloxy)phenyl,    4-(but-2-yn-1-yloxy)phenyl, 2-chloro-6-(prop-2-yn-1-yloxy)phenyl,    2-chloro-6-(2-methoxyethoxy)phenyl, 2-(allyloxy)-6-chlorophenyl,    2-[(2,2,2-trifluoro-ethoxy)methyl]phenyl,    2-[(ethylsulphonyl)methyl]phenyl or 2-(hydroxymethyl)phenyl, and R²    is especially phenyl, 2-fluorophenyl or 2,6-difluorophenyl,-   R³ is hydrogen,-   R^(Tz) is hydrogen,-   and agrochemically active salts, metal complexes and N-oxides    thereof.

According to the type of substituents defined above, the compounds ofthe formula (I) have acidic or basic properties and can form salts, ifappropriate also internal salts or adducts, with inorganic or organicacids or with bases or with metal ions. If the compounds of the formula(I) bear amino, alkylamino or other groups which induce basicproperties, these compounds can be reacted with acids to give salts, orthey are obtained directly as salts in the synthesis. If the compoundsof the formula (I) bear hydroxyl, carboxyl or other groups which induceacidic properties, these compounds can be reacted with bases to givesalts. Suitable bases are, for example, hydroxides, carbonates,hydrogencarbonates of the alkali metals and alkaline earth metals,especially those of sodium, potassium, magnesium and calcium, and alsoammonia, primary, secondary and tertiary amines having C₁-C₄-alkylgroups, mono-, di- and trialkanolamines of C₁-C₄-alkanols, choline andchlorocholine.

The salts obtainable in this way likewise have fungicidal, herbicidaland insecticidal properties.

Examples of inorganic acids are hydrohalic acids, such as hydrogenfluoride, hydrogen chloride, hydrogen bromide and hydrogen iodide,sulphuric acid, phosphoric acid and nitric acid, and acidic salts suchas NaHSO₄ and KHSO₄. Useful organic acids are, for example, formic acid,carbonic acid and alkanoic acids such as acetic acid, trifluoroaceticacid, trichloroacetic acid and propionic acid, and also glycolic acid,thiocyanic acid, lactic acid, succinic acid, citric acid, benzoic acid,cinnamic acid, oxalic acid, saturated or mono- or diunsaturated C₆-C₂₀fatty acids, alkylsulphuric monoesters, alkylsulphonic acids (sulphonicacids having straight-chain or branched alkyl radicals having 1 to 20carbon atoms), arylsulphonic acids or aryldisulphonic acids (aromaticradicals, such as phenyl and naphthyl, which bear one or two sulphonicacid groups), alkylphosphonic acids (phosphonic acids havingstraight-chain or branched alkyl radicals having 1 to 20 carbon atoms),arylphosphonic acids or aryldiphosphonic acids (aromatic radicals, suchas phenyl and naphthyl, which bear one or two phosphonic acid radicals),where the alkyl and aryl radicals may bear further substituents, forexample p-toluenesulphonic acid, salicylic acid, p-aminosalicylic acid,2-phenoxybenzoic acid, 2-acetoxybenzoic acid, etc.

Useful metal ions are especially the ions of the elements of the secondmain group, especially calcium and magnesium, of the third and fourthmain groups, especially aluminium, tin and lead, and also of the firstto eighth transition groups, especially chromium, manganese, iron,cobalt, nickel, copper, zinc and others. Particular preference is givento the metal ions of the elements of the fourth period. These metals maybe present in the different valencies that they can assume.

Optionally substituted groups may be mono- or polysubstituted, where thesubstituents in the case of polysubstitutions may be the same ordifferent.

In the definitions of the symbols given in the formulae above,collective terms were used which are generally representative of thefollowing substituents:

halogen: fluorine, chlorine, bromine and iodine;

alkyl: saturated, straight-chain or branched hydrocarbon radicals having1 to 8 carbon atoms, for example (but not limited to) C₁-C₆-alkyl suchas methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl,2-methylpropyl, 1,1-dimethylethyl, pentyl, 1-methylbutyl, 2-methylbutyl,3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, hexyl,1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl,3-methylpentyl 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl,1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl,3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl,1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl and1-ethyl-2-methylpropyl;

alkenyl: unsaturated, straight-chain or branched hydrocarbon radicalshaving 2 to 8 carbon atoms and one double bond in any position, forexample (but not limited to) C₂-C₆-alkenyl such as ethenyl, 1-propenyl,2-propenyl, 1-methylethenyl, 1-butenyl, 2-butenyl, 3-butenyl,1-methyl-1-propenyl, 2-methyl-1-propenyl, 1-methyl-2-propenyl,2-methyl-2-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl,1-methyl-1-butenyl, 2-methyl-1-butenyl, 3-methyl-1-butenyl,1-methyl-2-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl,1-methyl-3-butenyl, 2-methyl-3-butenyl, 3-methyl-3-butenyl,1,1-dimethyl-2-propenyl, 1,2-dimethyl-1-propenyl,1,2-dimethyl-2-propenyl, 1-ethyl-1-propenyl, 1-ethyl-2-propenyl,1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl,1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 3-methyl-1-pentenyl,4-methyl-1-pentenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl,3-methyl-2-pentenyl, 4-methyl-2-pentenyl, 1-methyl-3-pentenyl,2-methyl-3-pentenyl, 3-methyl-3-pentenyl, 4-methyl-3-pentenyl,1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 3-methyl-4-pentenyl,4-methyl-4-pentenyl, 1,1-dimethyl-2-butenyl, 1,1-dimethyl-3-butenyl,1,2-dimethyl-1-butenyl, 1,2-dimethyl-2-butenyl, 1,2-dimethyl-3-butenyl,1,3-dimethyl-1-butenyl, 1,3-dimethyl-2-butenyl, 1,3-dimethyl-3-butenyl,2,2-dimethyl-3-butenyl, 2,3-dimethyl-1-butenyl, 2,3-dimethyl-2-butenyl,2,3-dimethyl-3-butenyl, 3,3-dimethyl-1-butenyl, 3,3-dimethyl-2-butenyl,1-ethyl-1-butenyl, l-ethyl-2-butenyl, 1-ethyl-3-butenyl,2-ethyl-1-butenyl, 2-ethyl-2-butenyl, 2-ethyl-3-butenyl,1,1,2-trimethyl-2-propenyl, 1-ethyl-1-methyl-2-propenyl,1-ethyl-2-methyl-1-propenyl and 1-ethyl-2-methyl-2-propenyl;

alkynyl: straight-chain or branched hydrocarbon groups having 2 to 8carbon atoms and one triple bond in any position, for example (but notlimited to) C₂-C₆-alkynyl such as ethynyl, 1-propynyl, 2-propynyl,1-butynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 1-pentynyl,2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-2-butynyl,1-methyl-3-butynyl, 2-methyl-3-butynyl, 3-methyl-1-butynyl,1,1-dimethyl-2-propynyl, 1-ethyl-2-propynyl, 1-hexynyl, 2-hexynyl,3-hexynyl, 4-hexynyl, 5-hexynyl, 1-methyl-2-pentynyl,1-methyl-3-pentynyl, 1-methyl-4-pentynyl, 2-methyl-3-pentynyl,2-methyl-4-pentynyl, 3-methyl-1-pentynyl, 3-methyl-4-pentynyl,4-methyl-1-pentynyl, 4-methyl-2-pentynyl, 1,1-dimethyl-2-butynyl,1,1-dimethyl-3-butynyl, 1,2-dimethyl-3-butynyl, 2,2-dimethyl-3-butynyl,3,3-dimethyl-1-butynyl, 1-ethyl-2-butynyl, 1-ethyl-3-butynyl,2-ethyl-3-butynyl and 1-ethyl-1-methyl-2-propynyl;

alkoxy: saturated, straight-chain or branched alkoxy radicals having 1to 8 carbon atoms, for example (but not limited to) C₁-C₆-alkoxy such asmethoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 1-methylpropoxy,2-methylpropoxy, 1,1-dimethylethoxy, pentoxy, 1-methylbutoxy,2-methylbutoxy, 3-methylbutoxy, 2,2-dimethylpropoxy, 1-ethylpropoxy,hexoxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, 1-methylpentoxy,2-methylpentoxy, 3-methylpentoxy, 4-methylpentoxy, 1,1-dimethylbutoxy,1,2-dimethylbutoxy, 1,3-dimethylbutoxy, 2,2-dimethylbutoxy,2,3-dimethylbutoxy, 3,3-dimethylbutoxy, 1-ethylbutoxy, 2-ethylbutoxy,1,1,2-trimethylpropoxy, 1,2,2-trimethylpropoxy, 1-ethyl-1-methylpropoxyand 1-ethyl-2-methylpropoxy;

alkylthio: saturated, straight-chain or branched alkylthio radicalshaving 1 to 8 carbon atoms, for example (but not limited to)C₁-C₆-alkylthio such as methylthio, ethylthio, propylthio,1-methylethylthio, butylthio, 1-methylpropylthio, 2-methylpropylthio,1,1-dimethylethylthio, pentylthio, 1-methylbutylthio, 2-methylbutylthio,3-methylbutylthio, 2,2-dimethylpropylthio, 1-ethylpropylthio, hexylthio,1,1-dimethylpropylthio, 1,2-dimethylpropylthio, 1-methylpentylthio,2-methylpentylthio, 3-methylpentylthio, 4-methylpentylthio,1,1-dimethylbutylthio, 1,2-dimethylbutylthio, 1,3-dimethylbutylthio,2,2-dimethylbutylthio, 2,3-dimethylbutylthio, 3,3-dimethylbutylthio,1-ethylbutylthio, 2-ethylbutylthio, 1,1,2-trimethylpropylthio,1,2,2-trimethylpropylthio, 1-ethyl-1-methylpropylthio and1-ethyl-2-methylpropylthio;

alkoxycarbonyl: an alkoxy group which has 1 to 6 carbon atoms (asspecified above) and is bonded to the skeleton via a carbonyl group(—CO—);

alkylsulphinyl: saturated, straight-chain or branched alkylsulphinylradicals having 1 to 8 carbon atoms, for example (but not limited to)C₁-C₆-alkylsulphinyl such as methylsulphinyl, ethylsulphinyl,propylsulphinyl, 1-methylethylsulphinyl, butylsulphinyl,1-methylpropylsulphinyl, 2-methylpropylsulphinyl,1,1-dimethylethylsulphinyl, pentylsulphinyl, 1-methylbutylsulphinyl,2-methylbutylsulphinyl, 3-methylbutylsulphinyl,2,2-dimethylpropylsulphinyl, 1-ethylpropylsulphinyl, hexylsulphinyl,1,1-dimethylpropylsulphinyl, 1,2-dimethylpropylsulphinyl,1-methylpentylsulphinyl, 2-methylpentylsulphinyl,3-methylpentylsulphinyl, 4-methylpentylsulphinyl, 1,1-dimethylbutylsulphinyl, 1,2-dimethylbutylsulphinyl,1,3-dimethylbutylsulphinyl, 2,2-dimethylbutylsulphinyl,2,3-dimethylbutylsulphinyl, 3,3-dimethylbutylsulphinyl,1-ethylbutylsulphinyl, 2-ethylbutylsulphinyl,1,1,2-trimethylpropylsulphinyl, 1,2,2-trimethylpropylsulphinyl,1-ethyl-1-methylpropylsulphinyl and 1-ethyl-2-methylpropylsulphinyl:

alkylsulphonyl: saturated, straight-chain or branched alkylsulphonylradicals having 1 to 8 carbon atoms, for example (but not limited to)C₁-C₆-alkylsulphonyl such as methylsulphonyl, ethylsulphonyl,propylsulphonyl, 1-methylethylsulphonyl, butylsulphonyl,1-methylpropylsulphonyl, 2-methylpropylsulphonyl,1,1-dimethylethylsulphonyl, pentylsulphonyl, 1-methylbutylsulphonyl,2-methylbutylsulphonyl, 3-methylbutylsulphonyl,2,2-dimethylpropylsulphonyl, 1-ethylpropylsulphonyl, hexylsulphonyl,1,1-dimethylpropylsulphonyl, 1,2-dimethylpropylsulphonyl,I-methylpentlsulphonyl, 2-methylpcntylsulphonyl,3-methylpentylsulphonyl, 4-methylpentylsulphonyl,1,1-dimethylbutylsulphonyl, 1,2-dimethylbutylsulphonyl,1,3-dimethylbutylsulphonyl, 2,2-dimethylbutylsulphonyl,2,3-dimethylbutylsulphonyl, 3,3-dimethylbutylsulphonyl,1-ethylbutylsulphonyl, 2-ethylbutylsulphonyl,1,1,2-trimethylpropylsulphonyl, 1,2,2-trimethylpropylsulphonyl,1-ethyl-1-methylpropylsulphonyl and 1-ethyl-2-methylpropylsulphonyl;

cycloalkyl: monocyclic, saturated hydrocarbon groups having 3 to 10carbon ring members, for example (but not limited to) cyclopropyl,cyclopentyl and cyclohexyl;

haloalkyl: straight-chain or branched alkyl groups having 1 to 8 carbonatoms (as specified above), where some or all of the hydrogen atoms inthese groups may be replaced by halogen atoms as specified above, forexample (but not limited to) C₁-C₃-haloalkyl such as chloromethyl,bromomethyl, dichloromethyl, trichloromethyl, fluoromethyl,difluoromethyl, trifluoromethyl, chlorofluoromethyl,dichlorofluoromethyl, chlorodifluoromethyl, 1-chloroethyl, 1-bromoethyl,1-fluoroethyl 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl,2-chloro-2-fluoroethyl, 2-chloro-2,2-difluoroethyl,2,2-dichloro-2-fluoroethyl, 2,2,2-trichloroethyl, pentafluoroethyl and1,1,1-trifluoroprop-2-yl;

haloalkoxy: straight-chain or branched alkoxy groups having 1 to 8carbon atoms (as specified above), where some or all of the hydrogenatoms in these groups may be replaced by halogen atoms as specifiedabove, for example (but not limited to) C₁-C₃-haloalkoxy, such aschloromethoxy, bromomethoxy, dichloromethoxy, trichloromethoxy,fluoromethoxy, difluoromethoxy, trifluoromethoxy, chlorofluoromethoxy,dichlorofluoromethoxy, chlorodifluoromethoxy, 1-chloroethoxy,1-bromoethoxy, 1-fluoroethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy,2,2,2-trifluoroethoxy, 2-chloro-2-fluoroethoxy,2-chloro-2,2-difluoroethoxy, 2,2-dichloro-2-fluoroethoxy,2,2,2-trichloroethoxy, pentafluoroethoxy and 1,1,1-trifluoroprop-2-oxy;

haloalkylthio: straight-chain or branched alkylthio groups having 1 to 8carbon atoms (as specified above), where some or all of the hydrogenatoms in these groups may be replaced by halogen atoms as specifiedabove, for example (but not limited to) C₁-C₃-haloalkylthio, such aschloromethylthio, bromomethylthio, dichloromethylthio,trichloromethylthio, fluoromethylthio, difluoromethylthio,trifluoromethylthio, chlorofluoromethylthio, dichlorofluoromethylthio,chlorodifluoromethylthio, 1-chloroethylthio, 1-bromoethylthio,1-fluoroethylthio, 2-fluoroethylthio, 2,2-difluoroethylthio,2,2,2-trifluoroethylthio, 2-chloro-2-fluoroethylthio,2-chloro-2,2-difluoroethylthio, 2,2-dichloro-2-fluoroethylthio,2,2,2-trichloroethylthio, pentafluoroethylthio and1,1,1-trifluoroprop-2-ylthio;

heteroaryl: 5 or 6-membered fully unsaturated monocyclic ring systemcontaining one to four heteroatoms from the group of oxygen, nitrogenand sulphur; if the ring contains two or more oxygen atoms, they are notdirectly adjacent.

5-membered heteroaryl: containing one to four nitrogen atoms or one tothree nitrogen atoms and one sulphur or oxygen atom: 5-memberedheteroaryl groups which, in addition to carbon atoms, may contain one tofour nitrogen atoms or one to three nitrogen atoms and one sulphur oroxygen atom as ring members, for example (but not limited to) 2-furyl,3-furyl, 2-thienyl, 3-thienyl, 2-pyrrolyl, 3-pyrrolyl, 3-isoxazolyl,4-isoxazolyl, 5-isoxazolyl, 3-isothiazolyl, 4-isothiazolyl,5-isothiazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 2-oxazolyl,4-oxazolyl, 5-oxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl,2-imidazolyl, 4-imidazolyl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl,1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl, 1,2,4-triazol-3-yl,1,3,4-oxadiazol-2-yl, 1,3,4-thiadiazol-2-yl and 1,3,4-triazol-2-yl:

5-membered heteroaryl which contains one to four nitrogen atoms and isattached via nitrogen, or benzofused 5-membered heteroaryl whichcontains one to three nitrogen atoms and is attached via nitrogen:5-membered heteroaryl groups which, in addition to carbon atoms, maycontain one to four nitrogen atoms or one to three nitrogen atoms asring members, and in which two adjacent carbon ring members or onenitrogen and one adjacent carbon ring member may be bridged by abuta-1,3-diene-1,4-diyl group in which one or two carbon atoms may bereplaced by nitrogen atoms, where these rings are bonded to the skeletonvia one of the nitrogen ring members, for example (but not limited to)1-pyrrolyl, 1-pyrazolyl, 1,2,4-triazol-1-yl, 1-imidazolyl,1,2,3-triazol-1-yl and 1,3,4-triazol-1-yl;

6-membered heteroaryl containing one to four nitrogen atoms: 6-memberedheteroaryl groups which, in addition to carbon atoms, may contain one tothree or one to four nitrogen atoms as ring members, for example (butnot limited to) 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 3-pyridazinyl,4-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 2-pyrazinyl,1,3,5-triazin-2-yl, 1,2,4-triazin-3-yl and 1,2,4,5-tetrazin-3-yl;

benzofused 5-membered heteroaryl which contains one to three nitrogenatoms or one nitrogen atom and one oxygen or sulphur atom: for example(but not limited to) indol-1-yl, indol-2-yl, indol-3-yl, indol-4-yl,indol-5-yl, indol-6-yl, indol-7-yl, benzimidazol-1-yl,benzimidazol-2-yl, benzimidazol-4-yl, benzimidazol-5-yl, indazol-1-yl,indazol-3-yl, indazol-4-yl, indazol-5-yl, indazol-6-yl, indazol-7-yl,indazol-2-yl, 1-benzofuran-2-yl, 1-benzofuran-3-yl, 1-benzofuran-4-yl,1-benzofuran-5-yl, 1-benzofuran-6-yl, 1-benzofuran-7-yl1-benzothiophen-2-yl, 1-benzothiophen-3-yl, 1-benzothiophen-4-yl,1-benzothiophen-5-yl, 1-benzothiophen-6-yl, 1-benzothiophen-7-yl,1,3-benzothiazol-2-yl, 1,3-benzothiazol-4-yl, 1,3-benzothiazol-5-yl,1,3-benzothiazol-6-yl, 1,3-benzothiazol-7-yl, 1,3-benzoxazol-2-yl,1,3-benzoxazol-4-yl, 1,3-benzoxazol-5-yl, 1,3-benzoxazol-6-yl and1,3-benzoxazol-7-yl;

benzofused 6-membered heteroaryl containing one to three nitrogen atoms:for example (but not limited to) quinolin-2-yl, quinolin-3-ylquinolin-4-yl, quinolin-5-yl, quinolin-6-yl, quinolin-7-yl,quinolin-8-yl, isoquinolin-1-yl, isoquinolin-3-yl, isoquinolin-4-yl,isoquinolin-5-yl, isoquinolin-6-yl, isoquinolin-7-yl andisoquinolin-8-yl;

heterocyclyl: a three- to fifteen-membered saturated or partiallyunsaturated heterocycle containing one to four heteroatoms from thegroup of oxygen, nitrogen and sulphur: mono-, bi- or tricyclicheterocycles which contain, in addition to carbon ring members, one tothree nitrogen atoms and/or one oxygen or sulphur atom or one or twooxygen and/or sulphur atoms; if the ring contains two or more oxygenatoms, they are not directly adjacent; for example (but not limited to)oxiranyl, aziridinyl, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl,2-tetrahydrothienyl, 3-tetrahydrothienyl, 2-pyrrolidinyl,3-pyrrolidinyl, 3-isoxazolidinyl, 4-isoxazolidinyl, 5-isoxazolidinyl,3-isothiazolidinyl, 4-isothiazolidinyl, 5-isothiazolidinyl,3-pyrazolidinyl, 4-pyrazolidinyl, 5-pyrazolidinyl, 2-oxazolidinyl,4-oxazolidinyl, 5-oxazolidinyl, 2-thiazolidinyl, 4-thiazolidinyl,5-thiazolidinyl, 2-imidazolidinyl, 4-imidazolidinyl,1,2,4-oxadiazolidin-3-yl, 1,2,4-oxadiazolidin-5-yl,1,2,4-thiadiazolidin-3-yl, 1,2,4-thiadiazolidin-5-yl,1,2,4-triazolidin-3-yl, 1,3,4-oxadiazolidin-2-yl,1,3,4-thiadiazolidin-2-yl, 1,3,4-triazolidin-2-yl, 2,3-dihydrofur-2-yl,2,3-dihydrofur-3-yl, 2,4-dihydrofur-2-yl, 2,4-dihydrofur-3-yl,2,3-dihydrothien-2-yl, 2,3-dihydrothien-3-yl, 2,4-dihydrothien-2-yl,2,4-dihydrothien-3-yl, 2-pyrrolin-2-yl, 2-pyrrolin-3-yl,3-pyrrolin-2-yl, 3-pyrrolin-3-yl, 2-isoxazolin-3-yl, 3-isoxazolin-3-yl,4-isoxazolin-3-yl, 2-isoxazolin-4-yl, 3-isoxazolin-4-yl,4-isoxazolin-4-yl, 2-isoxazolin-5-yl, 3-isoxazolin-5-yl,4-isoxazolin-5-yl, 2-isothiazolin-3-yl, 3-isothiazolin-3-yl,4-isothiazolin-3-yl, 2-isothiazolin-4-yl, 3-isothiazolin-4-yl,4-isothiazolin-4-yl, 2-isothiazolin-5-yl, 3-isothiazolin-5-yl,4-isothiazolin-5-yl, 2,3-dihydropyrazol-1-yl, 2,3-dihydropyrazol-2-yl,2,3-dihydropyrazol-3-yl, 2,3-dihydropyrazol-4-yl,2,3-dihydropyrazol-5-yl 3,4-dihydropyrazol-1-yl,3,4-dihydropyrazol-3-yl, 3,4-dihydropyrazol-4-yl,3,4-dihydropyrazol-5-yl, 4,5-dihydropyrazol-1-yl,4,5-dihydropyrazol-3-yl, 4,5-dihydropyrazol-4-yl,4,5-dihydropyrazol-5-yl, 2,3-dihydrooxazol-2-yl, 2,3-dihydrooxazol-3-yl,2,3-dihydrooxazol-4-yl, 2,3-dihydrooxazol-5-yl, 3,4-dihydrooxazol-2-yl,3,4-dihydrooxazol-3-yl, 3,4-dihydrooxazol-4-yl, 3,4-dihydrooxazol-5-yl,3,4-dihydrooxazol-2-yl, 3,4-dihydrooxazol-3-yl, 3,4-dihydrooxazol-4-yl,2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 1,3-dioxan-5-yl,2-tetrahydropyranyl, 4-tetrahydropyranyl, 2-tetrahydrothienyl,3-hexahydropyridazinyl, 4-hexahydropyridazinyl, 2-hexahydropyrimidinyl,4-hexahydropyrimidinyl, 5-hexahydropyrimidinyl, 2-piperazinyl,1,3,5-hexahydrotriazin-2-yl and 1,2,4-hexahydrotriazin-3-yl:

leaving group: S_(N)1 or S_(N)2 leaving group, for example chlorine,bromine, iodine, alkylsulphonates (—OSO₂-alkyl, e.g. —OSO₂CH₃, —OSO₂CF₃)or arylsulphonates (—OSO₂-aryl, e.g. —OSO₂Ph, —OSO₂PhMe).

In the naming of combinations of a plurality of radicals, for exampleCx-Cy-alkylcarbonyl or Cx-Cy-alkoxyalkyl, the expression Cx-Cy in eachcase denotes the sum total of all carbon atoms present in the overallfragment in each case. X and Y are each whole numbers, where the numberY is greater than the number X.

Not included are combinations which contravene natural laws and whichthe person skilled in the art would therefore exclude based on his/herexpert knowledge. Ring structures having three or more adjacent oxygenatoms, for example, are excluded.

Illustration of the Processes and Intermediates

The bis(difluoromethyl)pyrazole derivatives of the formula (I) can beprepared in different ways. First of all, the possible processes areshown schematically hereinafter. Unless stated otherwise, the radicalsstated are each as defined above.

Process A

Process A describes the preparation of compounds of the structure (IV)by reaction of compounds of the structure (II) with (HI).

One means of preparing the intermediate (IV) from compound (II) is shownin Scheme 1 (Process A). A compound of the general formula (IV) isobtained from a compound of the general formula (III) by halogen-metalexchange and subsequent addition of a compound of the formula (II) (see,for example, Org. Lett. 2004, 6, 3083-3085).

Process A is performed in the presence of a suitable organometalliccompound. Preferred organometallic compounds are organolithium compounds(for example butyllithium) or Grignard reagents (for exampleisopropylmagnesium halide).

Process A is preferably performed using one or more diluents. Usefulsolvents in the performance of the process are preferably aproticsolvents, for example dioxane, glyme, diethyl ether or tetrahydrofuran.Particular preference is given to the use of tetrahydrofuran.

In the performance of process A, the reaction temperatures can be variedwithin a relatively wide range. In the case of the halogen-metalexchange reactions, the temperatures employed are generally from −120°C., to +150° C., preferably temperatures from −120° C., to +60° C., mostpreferably −120° C., to 0° C. After the addition of compound (II),preference is given to working at −80° C., to +50° C.

To perform process A, generally from 1 to 2 mol, preferably 1 mol, ofthe organometallic compound are used per mole of compound of the formula(III). The reaction time is 1 to 48 hours. The workup is effected by thecustomary methods. If necessary, the compounds are purified byrecrystallization, distillation or chromatography, or can optionallyalso be used in the next step without prior purification.

Process B

Process B describes the preparation of compounds of the structure (V-a)by halogenating compounds of the structure (IV).

A compound of the general formula (V-a) in which R^(1a)=F, Cl, Br and Iis obtained from a compound of the general formula (IV) by halogenation(see, for example, WO 06/133216, WO 04/108692, J. Med. Chem., 1991, 34,108-122, EP0796846, J. Antibiot., 1988, 41, 134-138, Bioorg. Med. Chem.Lett., 2008, 18, 5209-5212. Chem. Eur. J., 2004, 5640-5648, Russ. J.Org. Chem., 2007, 50-55).

The solvents used may be all customary solvents which are inert underthe reaction conditions, or the reaction can be performed in mixtures oftwo or more of these solvents. Preference is given to using the solventdichloromethane.

The halogen source used may, for example, be diethylaminosulphurtrifluoride, Selectfluor, Deoxofluor, thionyl chloride, PBr₃ andmethanesulphonyl chloride.

The starting materials and the halogenating agent are used in equimolaramounts. The halogenating agent can also be used in excess. The reactionis normally performed at temperatures of −80° C. to +80° C., andpreferably at 0° C. to +40° C., but it can also be performed at refluxtemperature of the reaction mixture. The reaction time varies as afunction of the scale of the reaction and the reaction temperature, butis generally between a few minutes and 48 hours.

After the reaction has ended, the compounds (V-a) are separated from thereaction mixture by one of the customary separation techniques. Ifnecessary, the compounds are purified by recrystallization, distillationor chromatography, or can optionally also be used in the next stepwithout prior purification.

Process C

One means of preparing the intermediate (VI-a) from compound (V-a) isshown in Scheme 3 (Process C).

A compound of the general formula (VI-a) is obtained from a compound ofthe general formula (V-a) by halogen-metal exchange and subsequentaddition of an electrophile (e.g. DMF); see, for example, Tetrahedron,2006, 62, 9017-9037, Org. Lett. 2005, 7, 339-342; Synthesis, 1987, 11,998-1001.

Process C is performed in the presence of a suitable organometalliccompound. Preferred organometallic compounds are organolithium compounds(for example butyllithium).

Process C is preferably performed using one or more diluents. Usefulsolvents in the performance of process C are preferably aprotic solvents(for example dioxane, glyme, diethyl ether or tetrahydrofuran).Particular preference is given to diethyl ether.

In the performance of process A, the reaction temperatures can be variedwithin a relatively wide range. In the case of the halogen-metalexchange reactions, the temperatures employed are generally from −120°C., to +150° C., preferably temperatures from −120° C., to +60° C., mostpreferably −120° C., to −70° C. After the addition of compound (II),preference is given to working at −80° C., to +50° C.

To perform process C, generally 1 to 2 mol, preferably 1 mol, of theorganometallic compound and of the electrophile are used per mole ofcompound of the formula (V-a). The reaction time is 1 to 48 hours.Work-up is carried out by customary methods. If necessary, the compoundsare purified by recrystallization, distillation or chromatography, orcan optionally also be used in the next step without prior purification.

Process D

One means of preparing the intermediate (VIII) from compound (VI) isshown in Scheme 4 (Process D).

A compound of the general formula (VIII) is obtained by condensation ofan aldehyde of the formula (VI) with hydroxylamine (VII) and subsequentchlorination (see, for example, WO 05/0040159, WO 08/013622 andSynthesis 1987, 11, 998-1001).

In process D, aldehyde (VI) (VI where R¹═H is available from Maybridge)and hydroxylamine (VII) are first reacted (Scheme 4, step (a)). Thecorresponding oxime is subsequently chlorinated in the presence of asuitable chlorinating agent. Preferred chlorinating reagents areN-chlorosuccinimide, HClO and chlorine. After step (a) of process D, thereaction mixture can be worked up by customary methods or convertedfurther directly in step (b).

Process D is preferably performed using one or more diluents. In step(a) of process D according to the invention, preference is given tousing protic solvents, for example ethanol, as the solvent. After theformation of the corresponding oxime from compound (VI), the reactionmixture is diluted in step (b) with a further solvent, for exampletetrahydrofuran, and then admixed with aqueous sodium hypochlorite. Thechlorination can likewise be effected with the aid ofN-chlorosuccinimide in DMF.

In the performance of process D, the reaction temperatures can be variedwithin a relatively wide range. In general, the temperatures employedare from −10° C., to +150° C., preferably temperatures from 0° C., to+100° C., most preferably reflux temperature of the solvent in step (a),and 0° C., to 30° C., in step (b).

To perform process D, generally 1 to 2 mol, preferably 1 mol, ofhydroxylamine (VII) and generally 1 to 5 mol, preferably 1 mol, of achlorinating reagent are used per mole of compound of the formula (VI).The reaction time is 1 to 48 hours. The workup is effected by customarymethods. If necessary, the compounds are purified by recrystallization,distillation or chromatography, or can optionally also be used in thenext step without prior purification.

Process E

One means of preparing the intermediate (X-a) or the inventive compoundsof the formula (I-a) from compound (VIII) is shown in Scheme 5 (ProcessE).

A compound of the general formula (X-a) or (I-a) is obtained from analkene of the general formula (IX) and compound (VIII) by acycloaddition reaction (see, for example, WO08013622, and Synthesis,1987, 11, 998-1001).

The alkenes (IX) are commercially available or can be prepared fromcommercially available precursors by methods described in the literature(for example from ketones or aldehydes by a Wittig orHorner-Wadsworth-Emmons olefination: Chem. Rev. 1989, 89, 863-927 andJulia olefination: Tetrahedron Lett., 1973, 14, 4833-4836: Petersonolefination: J. Org. Chem. 1968, 33, 780).

Process E is performed in the presence of a suitable base. Preferredbases are tertiary amines (e.g. triethylamine), and alkali metal oralkaline earth metal carbonates, hydrogencarbonates and phosphates.

Process E is preferably performed using one or more diluents. In theperformance of process E, inert organic solvents are a preferred option(for example toluene and hexane). Water is likewise a possible solvent.Alternatively, process E can be performed in an excess of the alkene(IX).

Typically, a suitable base and the olefin (IX) are initially charged andcompound (VIII) is added. Alternatively, compounds (VIII) and (IX) areinitially charged and a suitable base is added.

In the performance of process E, the reaction temperatures can be variedwithin a relatively wide range. In general, the temperatures employedare from −120° C., to +150° C., preferably temperatures of −10° C., to+100° C., most preferably 0° C. to 30° C.

To perform process E, generally 0.5 to 5 mol, preferably 1 mol, of thealkene (IX) are used per mole of compound of the formula (VIII). Thereaction time is 1 to 48 hours. The workup is effected by customarymethods. If necessary, the compounds are purified by recrystallization,distillation or chromatography, or can optionally also be used in thenext step without prior purification.

Process F

One means of preparing the intermediate (X-b) or the inventive compoundsof the formula (I-b) from compound (VIII) is shown in Scheme 6 (ProcessF).

A compound of the general formula (X-b) or (I-b) is obtained from analkyne of the general formula (XI) and compound (VIII) by acycloaddition reaction (see, for example, WO 08/013622, WO 05/040159 andSynthesis, 1987, 11, 998-1001).

The alkynes (XI) are commercially available or can be prepared fromcommercially available precursors by methods described in the literature(for example from ketones or aldehydes by a Corey-Fuchs reaction:Tetrahedron Lett. 1972, 36, 3769-3772, Seyferth-Gilbert homologization:J. Org. Chem., 1996, 61, 2540-2541, or with Bestmann-Ohira's reagent:Synthesis 2004, 1, 59-62).

Process F is performed in the presence of a suitable base. Preferredbases are tertiary amines (e.g. triethylamine), and alkali metal oralkaline earth metal carbonates, hydrogencarbonates and phosphates.

Process F is preferably performed using one or more diluents. In theperformance of process F, inert organic solvents are a preferred option,for example toluene and hexane. Water is likewise a possible solvent.Alternatively, process F can be performed in an excess of the alkyne(XI).

Typically, a suitable base and the alkyne (XI) are initially charged andcompound (VIII) is added. Alternatively, compounds (VIII) and (XI) areinitially charged and a suitable base is added.

In the performance of process F, the reaction temperatures can be variedwithin a relatively wide range. In general, the temperatures employedare from −120° C., to +150° C., preferably temperatures of −10° C., to+100° C., most preferably 0° C., to 30° C.

To perform process F, generally 0.5 to 5 mol, preferably 1 mol, of thealkyne (XI) are used per mole of compound of the formula (VIII). Thereaction time is 1 to 48 hours. The workup is effected by customarymethods. If necessary, the compounds are purified by recrystallization,distillation or chromatography, or can optionally also be used in thenext step without prior purification.

Process G

One means of preparing compounds of the formula (XII) from correspondingcompounds (X) is shown in Scheme 7.

A compound of the formula (X) is converted to a compound of the formula(XII) by suitable methods for removing protecting groups, which aredescribed in the literature (“Protective Groups in Organic Syvnthesis”;Third Edition; 1999; 494-653, and literature cited therein).

tert-Butoxycarbonyl and benzyloxycarbonyl protecting groups can beremoved in an acidic medium (for example with hydrochloric acid ortrifluoroacetic acid). Acetyl protecting groups can be removed underbasic conditions (for example with potassium carbonate or caesiumcarbonate). Benzylic protecting groups can be removed by hydrogenolysiswith hydrogen in the presence of a catalyst (for example palladium onactivated carbon).

Useful solvents are all customary solvents which are inert under thereaction conditions, for example alcohols (e.g. methanol, ethanol,propanol), cyclic and acyclic ethers (e.g. diethyl ether,tetrahydrofuran, dioxane), aromatic hydrocarbons (e.g. benzene, toluene,xylene), halogenated hydrocarbons (e.g. dichloromethane, chloroform,carbon tetrachloride), halogenated aromatic hydrocarbons (e.g.chlorobenzene, dichlorobenzene), nitriles (e.g. acetonitrile),carboxylic esters (e.g. ethyl acetate), amides (e.g.N,N-dimethylformamide, N,N-dimethylacetamide), dimethyl sulphoxide,1,3-dimethyl-2-imidazolinone, water and acetic acid, or the reaction canbe performed in mixtures of two or more of these solvents.

Acids which can be used for this reaction of deprotection oft-butoxycarbonyl and benzyloxycarbonyl groups are, for example,trifluoroacetic acid, hydrochloric acid or other acids as described inthe literature (for example “Protective Groups in Organic Synthesis”;Third Edition; 1999; pp. 494-653).

The reaction is normally performed at temperatures of 0° C., to +150°C., and preferably at room temperature, but it can also be performed atreflux temperature of the reaction mixture. The reaction time varies asa function of the scale of the reaction and the reaction temperature,but is generally between half an hour and 72 hours.

After the reaction has ended, the compounds (XII) are separated from thereaction mixture by one of the customary separation techniques. Ifnecessary, the compounds are purified by recrystallization, distillationor chromatography, or can, if desired, also be used in the next stepwithout prior purification. It is also possible to isolate the compoundof the general formula (XII) as a salt, for example as a salt ofhydrochloric acid or of trifluoroacetic acid.

Process H

One means of preparing compounds of the formula (Ia) from correspondingcompounds (XII) is shown in Scheme 8.

A compound with the general formula (Ia) can be synthesized analogouslyto methods described in the literature (see, for example WO 07/147336),by a coupling reaction of a compound with the corresponding generalformula (XII) with a substrate of the general formula (XHIa) whereW^(2a)=chlorine, optionally in the presence of an acid scavenger/base.

Compounds (XIIIa) (W^(2a)=chlorine) or (XIIIb) (W^(2b)=OH) are eithercommercially available or can be prepared by processes described in theliterature (see, for example, WO 08/013622 and WO 08/013925). Inaddition, a substrate with the general formula (XIIIa) whereW^(2a)=chlorine can be prepared from the corresponding acid (W^(2b)=OH)by chlorination using processes known from the literature (e.g.Tetrahedron 2005, 61, 10827-10852, and literature cited therein).

The substituents R² can be modified by reaction methods which are commonknowledge to those skilled in the art at all stages of the synthesis inwhich they occur. For example, OH, NH₂ or SH functionalities can bealkylated by known methods with suitable halides or sulphates (see, forexample, J. March: Advanced Organic Chemistry—Reactions, Mechanisms, andStructures, 4th Ed. (1992). Wiley, New York, pages 388-390, 406-407,411-415), acrylated using suitable carboxylic acids, carbonyl chloridesor carboxylic anhydrides (see J. March: Advanced OrganicChemistry—Reactions, Mechanisms, and Structures, 4th Ed. (1992), Wiley,New York, pages 392-400, 409, 417-419) or sulphonylated using suitablesulphonyl chlorides (see J. March: Advanced Organic Chemistry—Reactions,Mechanisms, and Structures, 4th Ed. (1992), Wiley, New York, pages496-500). It is also possible to convert hydroxyl compounds withhalogenating agents to corresponding halides (see, for example, J.March: Advanced Organic Chemistry—Reactions, Mechanisms, and Structures,4th Ed. (1992), Wiley, New York, pages 431-434). These halides in turncan be etherified with the aid of suitable hydroxyl compounds (see, forexample, J. March: Advanced Organic Chemistry—Reactions, Mechanisms, andStructures, 4th Ed. (1992), Wiley, New York, pages 388-390). It is alsopossible to reduce carbonyl functionalities by familiar methods tocorresponding hydroxyl compounds (see, for example, J. March: AdvancedOrganic Chemistry—Reactions. Mechanisms, and Structures, 4th Ed. (1992),Wiley, New York, pages 443, 910-918) or, in the case of aldehydes, tocarboxylic acids (see, for example, J. March: Advanced OrganicChemistry—Reactions. Mechanisms, and Structures, 4th Ed. (1992). Wiley,New York, pages 701-703), which can in turn be converted to thecorresponding esters (see, for example, J. March: Advanced OrganicChemistry—Reactions, Mechanisms, and Structures, 4th Ed. (1992), Wiley,New York, pages 393-396). Finally, thioethers can be oxidized usingsuitable oxidizing agents to sulphoxides or sulphones (see, for example,J. March: Advanced Organic Chemistry—Reactions, Mechanisms, andStructures, 4th Ed. (1992), Wiley, New York, pages 1201-1202). Examplesof such reactions can be found in the synthesis part of thisapplication.

The solvents used may be all customary solvents which are inert underthe reaction conditions, for example cyclic and acyclic ethers (e.g.diethyl ether, tetrahydrofuran, dioxane), aromatic hydrocarbons (e.g.benzene, toluene, xylene), halogenated hydrocarbons (e.g.dichloromethane, chloroform, carbon tetrachloride), halogenated aromatichydrocarbons (e.g. chlorobenzene, dichlorobenzene) and nitriles (e.g.acetonitrile), or the reaction can be performed in mixtures of two ormore of these solvents. The preferred solvents are tetrahydrofuran anddichloromethane.

At least one equivalent of an acid scavenger/a base (for example Hünig'sbase, triethylamine or commercially available polymeric acid scavengers)is used, in relation to the starting material of the general formula(XII). If the starting material is a salt, at least two equivalents ofthe acid scavenger are required.

The reaction is normally performed at temperatures of 0° C. to 100° C.and preferably at 20° C. to 30° C., but it can also be performed atreflux temperature of the reaction mixture. The reaction time varies asa function of the scale of the reaction and the reaction temperature,but is generally between a few minutes and 48 hours.

After the reaction has ended, the compounds (I) are separated from thereaction mixture by one of the customary separation techniques. Ifnecessary, the compounds are purified by recrystallization, distillationor chromatography, or can optionally also be used in the next stepwithout prior purification.

Alternatively, a compound of the formula (Ia) can also be synthesizedfrom the corresponding compound of the formula (XII) with a substrate ofthe formula (XIIIb) where W^(2b)=OH in the presence of a couplingreagent, analogously to methods described in the literature (e.g.Tetrahedron 2005, 61, 10827-10852, and references cited therein).

Suitable coupling reagents are, for example, peptide coupling reagents(for example N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide mixed with4-dimethylaminopyridine. N-(3-dimethylaminopropyl)-N′-ethylcarbodiimidemixed with 1-hydroxybenzotriazole, bromotripyrrolidinophosphoniumhexafluorophosphate,O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate, etc.).

If appropriate, a base, for example triethylamine or Hünig's base, canbe used in the reaction.

The solvents used may be all customary solvents which are inert underthe reaction conditions, for example alcohols (e.g. methanol, ethanol,propanol), cyclic and acyclic ethers (e.g. diethyl ether,tetrahydrofuran, dioxane), aromatic hydrocarbons (e.g. benzene, toluene,xylene), halogenated hydrocarbons (e.g. dichloromethane, chloroform,carbon tetrachloride), halogenated aromatic hydrocarbons (e.g.chlorobenzene, dichlorobenzene), nitriles (e.g. acetonitrile) and amides(e.g. N,N-dimethylformamide. N,N-dimethylacetamide), or the reaction canbe performed in mixtures of two or more of these solvents. The preferredsolvent is dichloromethane.

The reaction is normally performed at temperatures of 0° C.-100° C. andpreferably at 0° C.-30° C., but it can also be carried out at refluxtemperature of the reaction mixture. The reaction time varies as afunction of the scale of the reaction and the reaction temperature, butis generally between a few minutes and 48 hours.

After the reaction has ended, the compounds (la) are separated from thereaction mixture by one of the customary separation techniques. Ifnecessary, the compounds are purified by recrystallization, distillationor chromatography, or can optionally also be used in the next stepwithout prior purification.

Process I

One means of preparing compounds of the formula (I-c) in whichX^(b)=sulphur from corresponding compounds (Ia) in which X^(a) is oxygenis shown in Scheme 9.

The solvents used may be all customary solvents which are inert underthe reaction conditions, for example alcohols (e.g. methanol, ethanolpropanol), cyclic and acyclic ethers (e.g. diethyl ether,tetrahydrofuran, dioxane), aromatic hydrocarbons (e.g. benzene, toluene,xylene), halogenated hydrocarbons (e.g. dichloromethane, chloroform,carbon tetrachloride), halogenated aromatic hydrocarbons (e.g.chlorobenzene, dichlorobenzene), nitriles (e.g. acetonitrile),carboxylic esters (e.g. ethyl acetate) and amides (e.g.N,N-dimethylformamide. N,N-dimethylacetamide), and the reaction can beperformed in mixtures of two or more of these solvents. The preferredsolvents are chloroform and 1,2-dimethoxyethane.

Suitable thionating reagents are, for example, Lawesson's reagent (seeTetrahedron 1986, 42, 6555-6564, Tetrahedron Lett. 1993, 46, 7459-7462)and phosphorus pentasulphide. The starting material and the thionatingreagent are used in equimolar amounts, but the thionating reagent mayoptionally also be used in excess.

The reaction is normally performed at temperatures of 0° C. to 150° C.and preferably at 0° C. to 100° C. but it can also be performed atreflux temperature of the reaction mixture. The reaction time varies asa function of the scale of the reaction and the reaction temperature,but is generally between a few minutes and 48 hours.

After the reaction has ended, the compounds (Ib) in which X^(b)=sulphurare separated from the reaction mixture by one of the customaryseparation techniques. If necessary, the compounds are purified byrecrystallization, distillation or chromatography.

Process J

One means of preparing the intermediate (X-d) or the inventive compoundsof the formula (I-d) from compound (X-a) or (I-a) is shown in Scheme 10(Process J).

A compound of the general formula (X-d) or (I-d) is obtained fromcompound (X-a) or (I-a) by halogenation (see, for example, WO 08/013622,WO 05/040159 and Synthesis, 1987, 11, 998-1001).

The solvents used may be all customary solvents which are inert underthe reaction conditions, such as cyclic and acyclic ethers (e.g. diethylether, tetrahydrofuran, dioxane), aromatic hydrocarbons (e.g. benzene,toluene, xylene), halogenated hydrocarbons (e.g. dichloromethane,chloroform, carbon tetrachloride), halogenated aromatic hydrocarbons(e.g. chlorobenzene, dichlorobenzene), nitriles (e.g. acetonitrile),carboxylic acids (e.g. acetic acid) and carboxylic esters (e.g. ethylacetate), and the reaction can be performed in mixtures of two or moreof these solvents. The preferred solvents are chloroform and aceticacid.

Preferred halogenating reagents are, for example, N-chlorosuccinimide.HCIO and chlorine (chlorinating reagents), N-bromosuccinimide, HBrO andbromine (brominating reagents), N-fluorodibenzenesulphonimide (NFSI) andF₂ (fluorinating reagents) or N-iodsuccinimide, ICl and iodine(iodinating reagents; see J. March: Advanced OrganicChemistry—Reactions. Mechanisms, and Structures, 4th Ed. (1992). Wiley.New York, pages 531-534; D. Kikelj, U. Urleb in Science of Synthesis, 11(2001), pages 749-751). The starting material and the halogenatingreagent are used in equimolar amounts, but the halogenating reagent canoptionally also be used in excess.

The reaction is normally performed at temperatures of −10° C., to +200°C., and preferably at 0° C., to 100° C., but it can also be performed atreflux temperature of the reaction mixture. The reaction time varies asa function of the scale of the reaction and of the reaction temperature,but is generally between a few minutes and 48 hours.

After the reaction has ended, the compounds (X-d) or (I-d) are separatedfrom the reaction mixture by one of the customary separation techniques.If necessary, the compounds are purified by recrystallization,distillation or chromatography.

The invention further provides for the non-medical use of the inventivebis(difluoromethyl)pyrazole derivatives for control of unwantedmicroorganisms.

The invention further provides a composition for controlling unwantedmicroorganisms, comprising at least one bis(difluoromethyl)pyrazolederivative according to the present invention.

The invention also relates to a method for controlling unwantedmicroorganisms, characterized in that the inventivebis(difluoromethyl)pyrazole derivatives are applied to themicroorganisms and/or in their habitat.

The invention further relates to seed which has been treated with atleast one inventive bis(difluoromethyl)pyrazole derivative.

The invention finally provides a method for protecting seed againstunwanted microorganisms by using seed treated with at least onebis(difluoromethyl)pyrazole derivative according to the presentinvention.

The inventive substances have potent microbicidal action and can be usedto control unwanted microorganisms, such as fungi and bacteria, in cropprotection and in the protection of materials.

The inventive bis(difluoromethyl)pyrazole derivatives of the formula (I)have very good fungicidal properties and can be used in crop protection,for example for controlling Plasmodiophoromycetes, Oomycetes,Chvtridiomycetes, Zygomycetes, Ascomycetes, Basidiomycetes andDeuteromycetes.

Bactericides can be used in crop protection, for example to controlPseudomonadaceae, Rhizobiaceae, Enterobacteriaceae, Corynebacteriaceaeand Streptomycetaceae.

The inventive fungicidal compositions can be used for curative orprotective control of phytopathogenic fungi. The invention thereforealso relates to curative and protective methods for controllingphytopathogenic fungi by means of use of the inventive activeingredients or compositions which are applied to the seed, the plant orplant parts, the fruit or the soil in which the plants grow.

The inventive compositions for controlling phytopathogenic fungi in cropprotection comprise an effective but non-phytotoxic amount of theinventive active ingredients. An “effective but non-phytotoxic amount”means an amount of the inventive composition which is sufficient foradequate control of the fungal disease of the plant or to eradicate thefungal disease completely, and which, at the same time, does not causeany significant symptoms of phytotoxicity. In general, this applicationrate may vary within a relatively wide range. It depends on severalfactors, for example on the fungus to be controlled, the plant, theclimatic conditions and the ingredients of the inventive compositions.

All plants and plant parts can be treated in accordance with theinvention. Plants are understood here to mean all plants and plantpopulations such as desired and unwanted wild plants or crop plants(including naturally occurring crop plants). Crop plants may be plantswhich can be obtained by conventional breeding and optimization methodsor by biotechnological and genetic engineering methods or combinationsof these methods, including the transgenic plants and including theplant varieties which can or cannot be protected by varietal propertyrights. Plant parts are understood to mean all parts and organs ofplants above and below the ground, such as shoot, leaf, flower and root,examples of which include leaves, needles, stalks, stems, flowers, fruitbodies, fruits, seeds, roots, tubers and rhizomes. Parts of plants alsoinclude harvested plants and vegetative and generative propagationmaterial, for example seedlings, tubers, rhizomes, cuttings and seeds.

The plants which can be treated in accordance with the invention includethe following: cotton, flax, grapevine, fruit, vegetables, such asRosaceae sp. (for example pome fruits such as apples and pears, but alsostone fruits such as apricots, cherries, almonds and peaches, and softfruits such as strawberries). Ribesioidae sp., Juglimdaceae sp.,Betulaceae sp., Anacardiaceae sp., Fagaceae sp., Moraceae sp., Oleaceaesp., Actinidacene sp. Lauraceae sp. Musaceae sp. (for example bananaplants and banana plantations), Rubiaceae sp. (for example coffee).Theaceae sp., Sterculiceae sp., Rutaceae sp. (for example lemons,oranges and grapefruit); Solanaceae sp. (for example tomatoes),Liliaceae sp., Asteraceae sp. (for example lettuce), Umbelliferae sp.,Cruciferae sp. Chenopodiaceae sp., Cucurbitaceae sp. (for examplecucumber), Alliaceae sp. (for example leeks, onions), Papilionaceae sp.(for example peas); major crop plants such as Grammineae sp. (forexample maize, turf, cereals such as wheat, rye, rice, barley, oats,millet and triticale). Asteraceae sp. (for example sunflower),Brassicaceae sp. (for example white cabbage, red cabbage, broccoli,cauliflower, Brussels sprouts, pak choi, kohlrabi, radishes, and oilseedrape, mustard, horseradish and cress). Fabacae sp. (for example beans,peanuts). Papilionaceae sp. (for example soybean), Solanaceae sp. (forexample potatoes), Chenopodiaceae sp. (for example sugar beet, fodderbeet, Swiss chard, beetroot); useful plants and ornamental plants ingardens and forests; and in each case genetically modified types ofthese plants.

Non-limiting examples of pathogens of fungal diseases which can betreated in accordance with the invention include the following:

diseases caused by powdery mildew pathogens, for example Blumeriaspecies, for example Blumeria graminis; Podosphaera species, for examplePodosphaera leucotricha; Sphaerotheca species, for example Sphaerothecafuliginea; Uncinula species, for example Uncinula necator;

diseases caused by rust disease pathogens, for example Gymnosporangiumspecies, for example Gymnosporangium sabinae; Hemileia species, forexample Hemileia vastatrix; Phakopsora species, for example Phakopsorapachyrhizi or Phakopsora meibomiae; Puccinia species, for examplePuccinia recondita, Puccinia graminis or Puccinia striiformis; Uromycesspecies, for example Uromyces appendiculatus;

diseases caused by pathogens from the group of the Oomycetes, forexample Albugo species, for example Albugo candida; Bremia species, forexample Bremia lactucae; Peronospora species, for example Peronosporapisi or P, brassicae; Phytophthora species, for example Phytophthorainfestans; Plasmopara species, for example Plasmopara viticola;Pseudoperonospora species, for example Pseudoperonospora humuli orPseudoperonospora cubensis; Pythium species, for example Pythiumultimum;

leaf blotch diseases and leaf wilt diseases caused, for example, byAlternaria species, for example Alternaria solani; Cercospora species,for example Cercospora beticola; Cladiosporium species, for exampleCladiosporium cucumerinum; Cochliobolus species, for exampleCochliobolus sativus (conidial form: Drechslera, syn: Helminthosporium)or Cochliobolus miyabeanus; Colletotrichum species, for exampleColletotrichum lindemuthanium; Cycloconium species, for exampleCycloconium oleaginum, Diaporthe species, for example Diaporthe citri;Elsinoe species, for example Elsinoe fawcettii; Gloeosporium species,for example Gloeosporium laeticolor; Glomerella species, for exampleGlomerella cingulata; Guignardia species, for example Guignardiabidwelli; Leptosphaeria species, for example Leptosphaeria maculans;Magnaporthe species, for example Magnaporthe grisea; Microdochiumspecies, for example Microdochium nivale; Mycosphaerella species, forexample Mycosphaerella graminicola, Mycosphaerella arachidicola orMycosphaerella fijiensis; Phaeosphaeria species, for examplePhaeosphaeria nodorum; Pyrenophora species, for example Pyrenophorateres or Pyrenophora tritici repentis; Ramularia species, for exampleRamularia collo-cygni or Ramularia areola; Rhynchosporium species, forexample Rhynchosporium secalis; Septoria species, for example Septoriaapii or Septoria lycopersici; Stagonospora species, for exampleStagonospora nodorum; Typhula species, for example Typhula incarnata;Venturia species, for example Venturia inacqualis;

root and stem diseases caused, for example, by Corticium species, forexample Corticium graminearum; Fusarium species, for example Fusariumoxysporum; Gaeumannomyces species, for example Gaeumannomyces graminis;Plasmodiophora species, for example Plasmodiophora brassicae;Rhizoctonia species, for example Rhizoctonia solani; Sarocladiumspecies, for example Sarocladium oryzae; Sclerotium species, for exampleSclerotium oryzae; Tapesia species, for example Tapesia acuformis;Thielaviopsis species, for example Thielaviopsis basicola;

ear and panicle diseases (including corn cobs) caused, for example, byAlternaria species, for example Alternaria spp.; Aspergillus species,for example Aspergillus flavus; Cladosporium species, for exampleCladosporium cladosporioides; Claviceps species, for example Clavicepspurpurea; Fusarium species, for example Fusarium culmorum; Gibberellaspecies, for example Gibberella zeae; Monographella species, for exampleMonographella nivalis; Stagonospora species, for example Stagonosporanodorum;

diseases caused by smut fungi, for example Sphacelotheca species, forexample Sphacelotheca reiliana; Tilletia species, for example Tilletiacaries or Tilletia controversa; Urocystis species, for example Urocystisocculta; Ustilago species, for example Ustilago nuda;

fruit rot caused, for example, by Aspergillus species, for exampleAspergillus flavus; Botrytis species, for example Botrytis cincrea;Penicillium species, for example Penicillium expansum or Penicilliumpurpurogenum; Rhizopus species, for example Rhizopus stolonifer;Sclerotinia species, for example Sclerotinia sclerotiorum; Verticiliumspecies, for example Verticilium alboatrum;

seed- and soil-borne rot and wilt diseases, and also seedling diseases,caused, for example, by Alternaria species, for example Alternariabrassicicola; Aphanomyces species, for example Aphanomyces euteiches;Ascochyta species, for example Ascochyta lentis; Aspergillus species,for example Aspergillus flavus; Cladosporium species, for exampleCladosporium herbarum; Cochliobolus species, for example Cochliobolussativus (conidial form: Drechslera. Bipolaris Syn: Helminthosporium);Colletotrichum species, for example Colletotrichum coccodes; Fusariumspecies, for example Fusarium culmorum; Gibberella species, for exampleGibberella zeae; Macrophomina species, for example Macrophominaphaseolina; Microdochium species, for example Microdochium nivale;Monographella species, for example Monographella nivalis; Penicilliumspecies, for example Penicillium expansum; Phoma species, for examplePhoma lingam; Phomopsis species, for example Phomopsis sojae;Phytophthora species, for example Phytophthora cactorum; Pyrenophoraspecies, for example Pyrenophora graminca; Pyricularia species, forexample Pyricularia oryzae, Pythium species, for example Pythiumultimum; Rhizoctonia species, for example Rhizoctonia solani; Rhizopusspecies, for example Rhizopus oryzae; Sclerotium species, for exampleSclerotium rolfsii; Septoria species, for example Septoria nodorum;Typhula species, for example Typhula incarnata; Verticillium species,for example Verticillium dahliae;

cancers, galls and witches' broom caused, for example, by Nectriaspecies, for example Nectria galligena;

wilt diseases caused, for example, by Monilinia species, for exampleMonilinia laxa;

deformations of leaves, flowers and fruits caused, for example, byExobasidium species, for example Exobasidium vexans; Taphrina species,for example Taphrina deformans;

degenerative diseases in woody plants, caused, for example, by Escaspecies, for example Phaeomoniella chlamydospora, Phaeoacremoniumaleophilum or Fomitiporia mediterranea; Ganoderma species, for exampleGanoderma boninense;

diseases of flowers and seeds caused, for example, by Botrytis species,for example Botrytis cinerea;

diseases of plant tubers caused, for example, by Rhizoctonia species,for example Rhizoctonia solani; Helminthosporium species, for exampleHelminthosporium solani;

diseases caused by bacterial pathogens, for example Xanthomonas species,for example Xanthomonas campestris pv. oryzae; Pseudomonas species, forexample Pseudomonas syringae pv. lachrymans; Erwinia species, forexample Erwinia amylovora.

Preference is given to controlling the following diseases of soybeans:

Fungal diseases on leaves, stems, pods and seeds caused, for example, byalternaria leaf spot (Alternaria spec, atrans tenuissima), anthracnose(Colletotrichum gloeosporoides dematium var. truncatum), brown spot(Septoria glycines), cercospora leaf spot and blight (Cercosporakikuchii), choanephora leaf blight (Choanephora infundibulifera trispora(Syn.)), dactuliophora leaf spot (Dactuliophora glycines), downy mildew(Peronospora manshurica), drechslera blight (Drechslera glycini),frogeye leaf spot (Cercospora sojina), leptosphaerulina leaf spot(Leptosphaerulina trifolii), phyllostica leaf spot (Phyllosticasojaecola), pod and stem blight (Phomopsis sojae), powdery mildew(Microsphaera diffusa), pyrenochaeta leaf spot (Pyrenochaeta glycines),rhizoctonia aerial, foliage, and web blight (Rhizoctonia solani), rust(Phakopsora pachyrhizi, Phakopsora meibomiae), scab (Sphacelomaglycines), stemphylium leaf blight (Stemphylium botyosum), target spot(Corynespora cassiicola).

Fungal diseases on roots and the stem base caused, for example, by blackroot rot (Calonectria crotalariae), charcoal rot (Macrophominaphaseolina). fusarium blight or wilt, root rot, and pod and collar rot(Fusarium oxysporum, Fusarium orthoceras. Fusarium semitectum, Fusariumequiseti), mycoleptodiscus root rot (Mycoleptodiscus terrestris),neocosmospora (Neocosmospora vasinfecta), pod and stem blight (Diaporthephaseolorum), stem canker (Diaporthe phaseolorum var. caulivora),phytophthora rot (Phytophthora megasperma), brown stem rot (Phialophoragregata), pythium rot (Pythium aphanidermatum, Pythium irregulare,Pythium debaryanum, Pythium myriotylum, Pythium ultimum), rhizoctoniaroot rot, stem decay, and damping-off (Rhizoctonia solani), sclerotiniastem decay (Sclerotinia sclerotiorum), sclerotinia southern blight(Sclerotinia rolfsii), thielaviopsis root rot (Thielaviopsis basicola).

The inventive active ingredients also have very good fortifying actionin plants. They are therefore suitable for mobilizing the defenses ofthe plant against attack by undesirable microorganisms.

Plant-strengthening (resistance-inducing) substances are understood tomean, in the present context, those substances which are capable ofstimulating the defense system of plants in such a way that the treatedplants, when subsequently inoculated with undesirable microorganisms,display a high degree of resistance to these microorganisms.

In the present case, undesirable microorganisms are understood to meanphytopathogenic fungi and bacteria. The inventive substances can thus beused to protect plants for a certain period after the treatment againstattack by the pathogens mentioned. The period for which protection isprovided generally extends over 1 to 10 days, preferably 1 to 7 days,after the treatment of the plants with the active ingredients.

The fact that the active ingredients are well tolerated by plants at theconcentrations necessary for controlling plant diseases permitstreatment of above-ground parts of plants, of propagation stock andseeds, and of the soil.

The inventive active ingredients can be used particularly successfullyfor controlling diseases in viticulture and potato, fruit and vegetablegrowing, for example especially against downy mildew fungi andOomycetes, for example Phytophthora, Plasmopara, Pseudoperonospora andPythium species.

The inventive active ingredients are also suitable for enhancing theyield of crops. In addition, they have low toxicity and are welltolerated by plants.

If appropriate, the inventive compounds can, at certain concentrationsor application rates, also be used as herbicides, safeners, growthregulators or compositions to improve plant properties, or asmicrobicides, for example as fungicides, antimycotics, bactericides,viricides (including compositions to counteract viroids) or ascompositions to counteract MLO (mycoplasma-like organisms) and RLO(rickettsia-like organisms). If appropriate, they can also be used asinsecticides. If appropriate, they can also be used as intermediates orprecursors for the synthesis of other active ingredients.

The inventive active ingredients, when they are well tolerated byplants, have favourable homcotherm toxicity and are well tolerated bythe environment, are suitable for protecting plants and plant organs,for enhancing harvest yields, for improving the quality of the harvestedmaterial in agriculture, in horticulture, in animal husbandry, inforests, in gardens and leisure facilities, in the protection of storedproducts and of materials, and in the hygiene sector. They may bepreferably used as crop protection compositions. They are effectiveagainst normally sensitive and resistant species, and against all orsome stages of development.

The inventive treatment of the plants and plant parts with the activeingredients or compositions is effected directly or by action on theirsurroundings, habitat or storage space by the customary treatmentmethods, for example by dipping, spraying, atomizing, irrigating,evaporating, dusting, fogging, broadcasting, foaming painting,spreading-on, watering (drenching), drip irrigating and, in the case ofpropagation material, especially in the case of seeds, also by dry seedtreatment, wet seed treatment, slurry treatment, by incrusting, bycoating with one or more coats, etc. It is also possible to apply theactive ingredients by the ultra-low volume method or to inject theactive ingredient preparation or the active ingredient itself into thesoil.

The inventive active ingredients or compositions can also be used in theprotection of materials, for protecting industrial materials againstattack and destruction by unwanted microorganisms, for example fungi.

Industrial materials in the present context are understood to meaninanimate materials which have been prepared for use in industry. Forexample, industrial materials which are to be protected by inventiveactive ingredients from microbial change or destruction may beadhesives, sizes, paper and board, textiles, leather, wood, paints andplastic articles, cooling lubricants and other materials which can beinfected with, or destroyed by, microorganisms. The range of materialsto be protected also includes parts of production plants, for examplecooling water circuits, which may be impaired by the proliferation ofmicroorganisms. In the context of the present invention, industrialmaterials preferably include adhesives, sizes, paper and board, leather,wood, paints, cooling lubricants and heat-transfer liquids, morepreferably wood. The inventive active ingredients or compositions mayprevent adverse effects such as rotting, decay, discolouration,decolouration or formation of mould.

The inventive method for controlling unwanted fungi can also be employedfor protecting storage goods. Storage goods are understood to meannatural substances of vegetable or animal origin, or processed productsthereof, which are of natural origin and for which long-term protectionis desired. Storage goods of vegetable origin, for example plants orplant parts, such as stems, leaves, tubers, seeds, fruits, grains, canbe protected in the freshly harvested state or after processing by(pre)drying, moistening, comminuting, grinding, pressing or roasting.Storage goods also include timber, whether unprocessed, such asconstruction timber, electricity poles and barriers, or in the form offinished products, such as furniture. Storage goods of animal originare, for example, hides, leather, furs and hairs. The inventive activeingredients may prevent adverse effects such as rotting, decay,discolouration, decolouration or formation of mould.

Microorganisms capable of degrading or changing the industrial materialsinclude, for example, bacteria, fungi, yeasts, algae and slimeorganisms. The inventive active ingredients are preferably effectiveagainst fungi, especially moulds, wood-discoloring and wood-destroyingfungi (Basidiomycetes), and against slime organisms and algae. Examplesinclude microorganisms of the following genera: Alternaria, such asAlternaria tenuis; Aspergillus, such as Aspergillus niger; Chaetomium,such as Chaetomium globosum; Coniophora, such as Coniophora puetana;Lentinus, such as Lentinus tigrinus; Penicillium, such as Penicilliumglaucum; Polyporus, such as Polyporus versicolor, Aureobasidium, such asAureobasidium pullulans; Sclerophoma, such as Sclerophoma pityophila;Trichoderma, such as Trichoderma viride; Escherichia, such asEscherichia coli; Pseudomonas, such as Pseudomonas aeruginosa;Staphylococcus, such as Staphylococcus aureus.

The present invention further relates to a composition for controllingunwanted microorganisms, comprising at least one of the inventivebis(difluoromethyl)pyrazole derivatives. These are preferably fungicidalcompositions which comprise agriculturally usable auxiliaries, solvents,carriers, surfactants or extenders.

According to the invention, a carrier is a natural or synthetic, organicor inorganic substance with which the active ingredients are mixed orbonded for better applicability, in particular for application to plantsor plant parts or seed. The carrier, which may be solid or liquid, isgenerally inert and should be usable in agriculture.

Useful solid carriers include: for example, ammonium salts and groundnatural minerals such as kaolins, clays, talc, chalk, quartz,attapulgite, montmorillonite or diatomaceous earth, and ground syntheticminerals, such as finely divided silica, alumina and silicates; suitablesolid carriers for granules are: for example, crushed and fractionatednatural rocks such as calcite, marble, pumice, sepiolite and dolomite,and also synthetic granules of inorganic and organic meals, and alsogranules of organic material such as paper, sawdust, coconut shells,corn cobs and tobacco stalks; suitable emulsifiers and/or foam formersare: for example, nonionic and anionic emulsifiers, such aspolyoxyethylene fatty acid esters, polyoxyethylene fatty alcohol ethers,for example alkylaryl polyglycol ethers, alkylsulphonates, alkylsulphates, arylsulphonates and also protein hydrolysates; suitabledispersants are nonionic and/or ionic substances, for example from theclasses of the alcohol-POE and/or -POP ethers, acid and/or POP-POEesters, alkylaryl and/or POP-POE ethers, fat and/or POP-POE adducts,POE- and/or POP-polyol derivatives, POE- and/or POP-sorbitan or -sugaradducts, alkyl or aryl sulphates, alkyl- or arylsulphonates and alkyl oraryl phosphates or the corresponding PO-ether adducts. Further suitableoligomers or polymers are, for example, those derived from vinylicmonomers, from acrylic acid, from EO and/or PO alone or in combinationwith, for example, (poly)alcohols or (polv)amines. It is also possibleto use lignin and its sulphonic acid derivatives, unmodified andmodified celluloses, aromatic and/or aliphatic sulphonic acids and alsotheir adducts with formaldehyde.

The active ingredients can be converted to the customary formulations,such as solutions, emulsions, wettable powders, water- and oil-basedsuspensions, powders, dusts, pastes, soluble powders, soluble granules,granules for broadcasting, suspoemulsion concentrates, natural compoundsimpregnated with active ingredient, synthetic substances impregnatedwith active ingredient, fertilizers and also microencapsulations inpolymeric substances.

The active ingredients can be applied as such, in the form of theirformulations or the use forms prepared therefrom, such as ready-to-usesolutions, emulsions, water- or oil-based suspensions, powders, wettablepowders, pastes, soluble powders, dusts, soluble granules, granules forbroadcasting, suspoemulsion concentrates, natural products impregnatedwith active ingredient, synthetic materials impregnated with activeingredient, fertilizers and also microencapsulations in polymericsubstances. Application is carried out in a customary manner, forexample by watering, spraying, atomizing, broadcasting, dusting,foaming, spreading, etc. It is also possible to apply the activeingredients by the ultra-low volume method, or to inject the activeingredient preparation or the active ingredient itself into the soil. Itis also possible to treat the seed of the plants.

The formulations mentioned can be prepared in a manner known per se, forexample by mixing the active ingredients with at least one customaryextender, solvent or diluent, emulsifier, dispersant and/or binder orfixing agent, wetting agent, a water repellent, if appropriatesiccatives and UV stabilizers and if appropriate dyes and pigments,antifoams, preservatives, secondary thickeners, stickers, gibberellinsand also other processing auxiliaries.

The inventive compositions include not only formulations which arealready ready for use and can be applied with a suitable apparatus tothe plant or the seed, but also commercial concentrates which have to bediluted with water prior to use.

The inventive active ingredients may be present as such or in their(commercial) formulations and in the use forms prepared from theseformulations as a mixture with other (known) active ingredients, such asinsecticides, attractants, sterilants, bactericides, acaricides,nematicides, fungicides, growth regulators, herbicides, fertilizers,safeners and/or semiochemicals.

The auxiliaries used may be those substances which are suitable forimparting particular properties to the composition itself and/or topreparations derived therefrom (for example spray liquors, seeddressings), such as certain technical properties and/or also particularbiological properties. Typical auxiliaries include: extenders, solventsand carriers.

Suitable extenders are, for example, water, polar and nonpolar organicchemical liquids, for example from the classes of the aromatic andnonaromatic hydrocarbons (such as paraffins, alkylbenzenes,alkylnaphthalenes, chlorobenzenes), the alcohols and polyols (which mayoptionally also be substituted, etherified and/or esterified), theketones (such as acetone, cyclohexanone), esters (including fats andoils) and (poly)ethers, the unsubstituted and substituted amines,amides, lactams (such as N-alkylpyrrolidones) and lactones, thesulphones and sulphoxides (such as dimethyl sulphoxide).

Liquefied gaseous extenders or carriers are understood to mean liquidswhich are gaseous at standard temperature and under standard pressure,for example aerosol propellants such as halohydrocarbons, or elsebutane, propane, nitrogen and carbon dioxide.

Tackifiers such as carboxymethylcellulose and natural and syntheticpolymers in the form of powders, granules or latices, such as gumarabic, polyvinyl alcohol and polyvinyl acetate, or else naturalphospholipids such as cephalins and lecithins and syntheticphospholipids can be used in the formulations. Other possible additivesare mineral and vegetable oils.

If the extender used is water, it is also possible to use, for example,organic solvents as auxiliary solvents. Useful liquid solvents areessentially: aromatics such as xylene, toluene or alkylnaphthalenes,chlorinated aromatics or chlorinated aliphatic hydrocarbons such aschlorobenzenes, chloroethylenes or methylene chloride, aliphatichydrocarbons such as cyclohexane or paraffins, for example petroleumfractions, alcohols such as butanol or glycol and their ethers andesters, ketones such as acetone, methyl ethyl ketone, methyl isobutylketone or cyclohexanone, strongly polar solvents such asdimethylformamide and dimethyl sulphoxide, or else water.

The inventive compositions may additionally comprise further components,for example surfactants. Useful surfactants include emulsifiers and/orfoam formers, dispersants or wetting agents with ionic or nonionicproperties, or mixtures of these surfactants. Examples of these aresalts of polyacrylic acid, salts of lignosulphonic acid, salts ofphenolsulphonic acid or naphthalenesulphonic acid, polycondensates ofethylene oxide with fatty alcohols or with fatty acids or with fattyamines, substituted phenols (preferably alkylphenols or arylphenols),salts of sulphosuccinic esters, taurine derivatives (preferably alkyltaurates), phosphoric esters of polyethoxylated alcohols or phenols,fatty esters of polyols, and derivatives of the compounds containingsulphates, sulphonates and phosphates, for example alkylaryl polyglycolethers, alkylsulphonates, alkyl sulphates, arylsulphonates, proteinhydrolysates, lignosulphite waste liquors and methylcellulose. Thepresence of a surfactant is required if one of the active ingredientsand/or one of the inert carriers is insoluble in water and when theapplication is effected in water. The proportion of surfactants isbetween 5 and 40 percent by weight of the inventive composition.

It is possible to use dyes such as inorganic pigments, for example ironoxide, titanium oxide and Prussian Blue, and organic dyes such asalizarin dyes, azo dyes and metal phthalocyanine dyes, and tracenutrients such as salts of iron, manganese, boron, copper, cobalt,molybdenum and zinc.

Other possible additives are perfumes, mineral or vegetable oils whichhave optionally been modified, waxes and nutrients (including tracenutrients), such as salts of iron, manganese, boron, copper, cobalt,molvbdenumn and zinc.

Stabilizers such as low-temperature stabilizers, preservatives,antioxidants, light stabilizers or other compositions which improvechemical and/or physical stability may also be present.

If appropriate, other additional components may also be present, forexample protective colloids, binders, adhesives, thickeners, thixotropicsubstances, penetrants, stabilizers, sequestrants, complexing agents. Ingeneral the active ingredients can be combined with any solid or liquidadditive customarily used for formulation purposes.

The formulations generally contain between 0.05 and 99% by weight, 0.01and 98% by weight, preferably between 0.1 and 95% by weight and morepreferably between 0.5 and 90% of active ingredient, most preferablybetween 10 and 70 percent by weight.

The formulations described above can be used in an inventive method forcontrolling unwanted microorganisms, in which the inventivebis(diluoromethyl)pyrazole derivatives are applied to the microorganismsand/or in their habitat.

The inventive active ingredients can also be used, as such or in theirformulations, in a mixture with known fungicides, bactericides,acaricides, nematicides or insecticides, in order thus to broaden, forexample, the activity spectrum or to prevent development of resistance.

Useful mixing partners include, for example, known fungicides,insecticides, acaricides, nematicides or else bactericides (see alsoPesticide Manual, 14th ed.).

A mixture with other known active ingredients, such as herbicides, orwith fertilizers and growth regulators, safeners and/or semiochemicalsis also possible.

The compounds are applied in a customary manner appropriate for the useforms.

The invention also includes a method for treating seed.

A further aspect of the present invention relates in particular to seedtreated with at least one of the inventive bis(diluoromethyl)pyrazolederivatives. The inventive seeds are used in methods for the protectionof seed from phytopathogenic harmful fungi. In these methods, seedtreated with at least one inventive active ingredient is used.

The inventive active ingredients or compositions are also suitable fortreating seed. A large part of the damage to crop plants caused byharmful organisms is triggered by the infection of the seed duringstorage or after sowing, and also during and after germination of theplant. This phase is particularly critical since the roots and shoots ofthe growing plant are particularly sensitive, and even only minor damagemay result in the death of the plant. There is therefore great interestin protecting the seed and the germinating plant by using appropriatecompositions.

The control of phytopathogenic harmful fungi by treating the seed ofplants has been known for a long time and is the subject of constantimprovements. However, the treatment of seed gives rise to a series ofproblems which cannot always be solved in a satisfactory manner. Thus,it is desirable to develop methods for protecting the seed and thegerminating plant which dispense with, or at least reduce considerably,the additional application of crop protection compositions after sowingor after emergence of the plants. It is also desirable to optimize theamount of active ingredient used in such a way as to provide optimumprotection for the seed and the germinating plant from attack byphytopathogenic fungi, but without damaging the plant itself by theactive ingredient employed. In particular, methods for the treatment ofseed should also take into consideration the intrinsic fungicidalproperties of transgenic plants in order to achieve optimum protectionof the seed and the germinating plant with a minimum of crop protectioncompositions being employed.

The present invention therefore also relates to a method for protectingseed and germinating plants from attack by animal pests and/orphytopathogenic harmful fungi by treating the seed with an inventivecomposition. The invention also relates to the use of the inventivecompositions for treating seed for protection of the seed and of thegerminating plant against phytopathogenic fungi. The invention furtherrelates to seed which has been treated with an inventive composition forprotection from phytopathogenic fungi.

The control of animal pests and/or phytopathogenic harmful fungi whichdamage plants post-emergence is effected primarily by treating the soiland the above-ground parts of plants with crop protection compositions.Owing to the concerns regarding a possible impact of the crop protectioncompositions on the environment and the health of humans and animals,there are efforts to reduce the amount of active ingredients applied.

One of the advantages of the present invention is that, because of theparticular systemic properties of the inventive compositions, treatmentof the seed with these compositions protects not only the seed itselfbut also the resulting plants after emergence from animal pests and/orphytopathogenic harmful fungi. In this manner, the immediate treatmentof the crop at the time of sowing or shortly thereafter can be dispensedwith.

It is also considered to be advantageous that the inventive activeingredients or compositions can be used especially also for transgenicseed where the plant growing from this seed is capable of expressing aprotein which acts against pests. By treating such seed with theinventive active ingredients or compositions, even the expression of theinsecticidal protein, for example, may control certain pests.Surprisingly, a further synergistic effect may be observed here, whichadditionally increases the effectiveness of the protection againstattack by pests.

The inventive compositions are suitable for protecting seed of any plantvariety which is employed in agriculture, in the greenhouse, in forestsor in horticulture. In particular, the seed is that of cereals (such aswheat, barley, rye, millet and oats), maize, cotton, soybeans, rice,potatoes, sunflowers, beans, coffee, beets (for example sugarbeets andfodder beets), peanuts, vegetables (such as tomatoes, cucumbers, onionsand lettuce), lawns and ornamental plants. The treatment of the seed ofcereals (such as wheat, barley, rye and oats), maize and rice is ofparticular importance.

As also described below, the treatment of transgenic seed with theinventive active ingredients or compositions is of particularimportance. This relates to the seed of plants containing at least oneheterologous gene which enables the expression of a polypeptide orprotein having insecticidal properties. The heterologous gene intransgenic seed may originate, for example, from microorganisms of theBacillus, Rhizobium, Pseudomonas, Serratia, Trichoderma, Clavibacter,Glomus or Gliocladium species. This heterologous gene preferablyoriginates from Bacillus sp., the gene product being effective againstthe European corn borer and/or the Western corn rootworm. Theheterologous gene more preferably originates from Bacillusthuringiensis.

In the context of the present invention, the inventive composition isapplied to the seed alone or in a suitable formulation. The seed ispreferably treated in a state in which it is stable enough that nodamage occurs during treatment. In general, the seed may be treated atany time between harvest and sowing. The seed typically used has beenseparated from the plant and freed from cobs, shells, stalks, coats,hairs or the flesh of the fruits. For example, it is possible to useseed which has been harvested, cleaned and dried to a moisture contentof less than 15% by weight. Alternatively, it is also possible to useseed which, after drying, has been treated, for example, with water andthen dried again.

When treating the seed, it must generally be ensured that the amount ofthe inventive composition and/or of further additives applied to theseed is selected such that the germination of the seed is not impaired,and the resulting plant is not damaged. This must be borne in mind inparticular in the case of active ingredients which can exhibitphytotoxic effects at certain application rates.

The inventive compositions can be applied directly, i.e. withoutcontaining any other components and without having been diluted. Ingeneral, it is preferable to apply the compositions to the seed in theform of a suitable formulation. Suitable formulations and methods fortreating seed are known to the person skilled in the art and aredescribed, for example, in the following documents: U.S. Pat. No.4,272,417 A, U.S. Pat. No. 4,245,432 A, U.S. Pat. No. 4,808,430 A, U.S.Pat. No. 5,876,739 A, US 2003/0176428 A1, WO 2002/080675 A1. WO2002/028186 A2.

The active ingredients which can be used in accordance with theinvention can be converted to the customary seed-dressing formulations,such as solutions, emulsions, suspensions, powders, foams, slurries orother coating compositions for seed, and also ULV formulations.

These formulations are prepared in a known manner, by mixing the activeingredients or active ingredient combinations with customary additives,for example customary extenders and also solvents or diluents, dyes,wetting agents, dispersants, emulsifiers, antifoams, preservatives,secondary thickeners, adhesives, gibberellins, and also water.

Dyes which may be present in the seed-dressing formulations usable inaccordance with the invention are all dyes which are customary for suchpurposes. In this context, it is possible to use either pigments, whichare sparingly soluble in water, or dyes, which are soluble in water.Examples include the dyes known by the names Rhodamine B, C.I. PigmentRed 112 and C.I. Solvent Red 1.

Suitable wetting agents which may be present in the seed-dressingformulations usable in accordance with the invention are all substanceswhich promote wetting and which are conventional in the formulation ofactive agrochemical ingredients. Preference is given to usingalkylnaphthalenesulphonates, such as diisopropyl- ordiisobutylnaphthalenesulphonates.

Useful dispersants and/or emulsifiers which may be present in theseed-dressing formulations usable in accordance with the invention areall nonionic, anionic and cationic dispersants conventional in theformulation of active agrochemical ingredients. Preference is given tousing nonionic or anionic dispersants or mixtures of nonionic or anionicdispersants. Suitable nonionic dispersants include especially ethyleneoxide/propylene oxide block polymers, alkylphenol polyglycol ethers andtristryrylphenol polyglycol ethers, and the phosphated or sulphatedderivatives thereof. Suitable anionic dispersants are especiallylignosulphonates, polyacrylic acid salts and arylsulphonate/formaldehydecondensates.

Antifoams which may be present in the seed-dressing formulations usablein accordance with the invention are all foam-inhibiting substancesconventional in the formulation of active agrochemical ingredients.Silicone antifoams and magnesium stearate can preferably be used.

Preservatives which may be present in the seed-dressing formulationsusable in accordance with the invention are all substances which can beused for such purposes in agrochemical compositions. Examples includedichlorophene and benzyl alcohol hemiformal.

Secondary thickeners which may be present in the seed-dressingformulations usable in accordance with the invention are all substancesuseful for such purposes in agrochemical compositions. Preference isgiven to cellulose derivatives, acrylic acid derivatives, xanthan,modified clays and finely divided silica.

Adhesives which may be present in the seed-dressing formulations usablein accordance with the invention are all customary binders usable inseed-dressing products. Preference is given to polyvinylpyrrolidone,polyvinyl acetate, polyvinyl alcohol and tylose.

The gibberellins which may be present in the seed-dressing formulationsusable in accordance with the invention may preferably be gibberellinsA1, A3 (=gibberellic acid), A4 and A7 particular preference is given tousing gibberellic acid. The gibberellins are known (cf. R. Wegler“Chemie der Pflanzenschutz- und Schädlingsbekämpfungsmittel” [Chemistryof Crop Protection Compositions and Pesticide Compositions], vol. 2,Springer Verlag, 1970, p. 401-412).

The seed-dressing formulations usable in accordance with the inventioncan be used for the treatment of a wide range of seed, either directlyor after preceding dilution with water. Thus, the concentrates or thepreparations obtainable therefrom by dilution with water can be used todress the seed of cereals, such as wheat, barley, rye, oats andtriticale, and also the seed of maize, rice, oilseed rape, peas, beans,cotton, sunflowers and beets, or else vegetable seed of a wide varietyof types. The seed-dressing formulations usable in accordance with theinvention or the dilute preparations thereof can also be used to dressseed of transgenic plants. In this context, additional synergisticeffects may also occur in interaction with the substances formed byexpression.

For treatment of seed with the seed-dressing formulations usable inaccordance with the invention or the formulations prepared therefrom byaddition of water, useful mixing equipment is all of that usableconventionally for the seed-dressing operation. Specifically, theprocedure during the seed-dressing operation is to place the seed into amixer, add the specific desired amount of seed-dressing formulations,either as such or after preceding dilution with water, and mix until theformulation is distributed homogeneously on the seed. If appropriate,this is followed by a drying process.

The application rate of the seed-dressing formulations usable inaccordance with the invention may be varied within a relatively widerange. It depends on the particular content of the active ingredients inthe formulations and on the seed. The application rates of activeingredient combination are generally between 0.001 and 50 g per kilogramof seed, preferably between 0.01 and 15 g per kilogram of seed.

In addition, the inventive compounds of the formula (I) also have verygood antimycotic activity. They have a very broad antimycotic activityspectrum, in particular against dermatophytes and yeasts, moulds anddiphasic fungi (for example against Candida species, such as Candidaalbicans, Candida glabrata), and Epidermophyton floccosum, Aspergillusspecies, such as Aspergillus niger and Aspergillus fumigatus,Trichophyton species, such as Trichophyton mentagrophytes, Microsporonspecies, such as Microsporon canis and audouinii. The list of thesefungi by no means constitutes a restriction in the mycotic spectrumcovered, and is merely of illustrative character.

The inventive active ingredients of the formula (I) can therefore beused both in medical and in non-medical applications.

The active ingredients can be used as such, in the form of theirformulations or the use forms prepared therefrom, such as ready-to-usesolutions, suspensions, wettable powders, pastes, soluble powders, dustsand granules. Application is carried out in a customary manner, forexample by watering, spraying, atomizing, broadcasting, dusting,foaming, spreading, etc. It is also possible to apply the activeingredients by the ultra-low volume method, or to inject the activeingredient preparation or the active ingredient itself into the soil. Itis also possible to treat the seed of the plants.

When the inventive active ingredients are used as fungicides, theapplication rates can be varied within a relatively wide range,depending on the kind of application. The application rate of theinventive active ingredients is

-   -   when treating plant parts, for example leaves: from 0.1 to 10        000 g/ha, preferably from 10 to 1000 g/ha, more preferably from        50 to 300 g/ha (in the case of application by watering or        dripping, it is even possible to reduce the application rate,        particularly when inert substrates such as rockwool or perlite        are used);    -   when treating seed: from 2 to 200 g per 100 kg of seed,        preferably from 3 to 150 g per 100 kg of seed, more preferably        from 2.5 to 25 g per 100 kg of seed, most preferably from 2.5 to        12.5 g per 100 kg of seed;    -   when treating the soil: from 0.1 to 10 000 g/ha, preferably from        1 to 5000 g/ha.

These application rates are mentioned merely by way of example and arenot limiting in the context of the invention.

The inventive active ingredients are employed in the veterinary sectorand in animal husbandry in a known manner by enteral administration inthe form of, for example, tablets, capsules, potions, drenches,granules, pastes, boluses, the feed-through process and suppositories,by parenteral administration, for example by injection (intramuscular,subcutaneous, intravenous, intraperitoneal and the like), implants, bynasal administration, by dermal use in the form, for example, of dippingor bathing, spraying, pouring on and spotting on, washing and powdering,and also with the aid of moulded articles containing the activeingredient, such as collars, ear marks, tail marks, limb bands, halters,marking devices and the like.

When used for livestock, poultry, domestic animals and the like, theactive ingredients of the formula (I) can be used as formulations (forexample powders, emulsions, flowables) comprising the active ingredientsin an amount of 1 to 80% by weight, either directly or after 100- to 10000-fold dilution, or they may be used as a chemical bath.

The ready-to-use compositions may also comprise other insecticides ifappropriate, and also one or more fungicides if appropriate.

With respect to possible additional partners for mixing, reference ismade to the insecticides and fungicides mentioned above.

The inventive compounds can additionally be employed for anti-foulingprotection of objects which come into contact with saltwater or brackishwater, such as hulls, screens, nets, buildings, moorings and signallingsystems in particular.

In addition, the inventive compounds can be used alone or incombinations with other active ingredients as anti-fouling compositions.

The inventive treatment method can be used for the treatment ofgenetically modified organisms (GMOs), e.g. plants or seeds. Geneticallymodified plants (or transgenic plants) are plants in which aheterologous gene has been stably integrated into the genome. Theexpression “heterologous gene” essentially means a gene which isprovided or assembled outside the plant and, when introduced in thenuclear, chloroplastic or mitochondrial genome, imparts new or improvedagronomic or other properties to the transformed plant by expressing aprotein or polypeptide of interest or by downregulating or silencing(an)other gene(s) present in the plant (for example by means ofantisense technology, cosuppression technology or RNAi technology [RNAinterference]). A heterologous gene present in the genome is also calleda transgene. A transgene defined by its specific location in the plantgenome is called a transformation or transgenic event.

Depending on the plant species or plant varieties, their location andgrowth conditions (soils, climate, vegetation period, diet), theinventive treatment may also result in superadditive (“synergistic”)effects. For example, the following are possible effects exceeding theeffects which were actually to be expected: reduced application ratesand/or a widening of the activity spectrum and/or an increase in theactivity of the active ingredients and compositions which can be used inaccordance with the invention, better plant growth, increased toleranceto high or low temperatures, increased tolerance to drought or to wateror soil salt content, increased flowering performance, easierharvesting, accelerated maturation, higher harvest yields, biggerfruits, larger plant height, greener leaf colour, earlier flowering,higher quality and/or a higher nutritional value of the harvestedproducts, higher sugar concentration within the fruits, better storagestability and/or processability of the harvested products.

At certain application rates, the inventive active ingredientcombinations may also have a strengthening effect on plants. They aretherefore suitable for mobilizing the defense system of the plantagainst attack by unwanted phytopathogenic fungi and/or microorganismsand/or viruses. This may in some cases be one of the reasons for theenhanced activity of the inventive combinations, for example againstfungi. Plant-strengthening (resistance-inducing) substances should beunderstood in the present context also to mean those substances orsubstance combinations which are capable of stimulating the defensesystem of plants in such a way that, when subsequently inoculated withunwanted phytopathogenic fungi and/or microorganisms and/or viruses, thetreated plants display a substantial degree of resistance to theseunwanted phytopathogenic fungi and/or microorganisms and/or viruses. Inthe present case, unwanted phytopathogenic fungi and/or microorganismsand/or viruses are understood to mean phytopathogenic fungi, bacteriaand viruses. The inventive substances can therefore be employed forprotection of plants from attack by the abovementioned pathogens withina certain period of time after the treatment. The period within whichprotection is achieved generally lasts for from 1 to 10 days, preferably1 to 7 days, after the treatment of the plants with the activeingredients.

Plants and plant varieties which are preferably treated in accordancewith the invention include all plants which have genetic material whichimparts particularly advantageous useful traits to these plants (whetherobtained by breeding and/or biotechnology).

Plants and plant varieties which are likewise preferably treated inaccordance with the invention are resistant to one or more biotic stressfactors, i.e. said plants have an improved defense against animal andmicrobial pests, such as nematodes, insects, mites, phytopathogenicfungi, bacteria, viruses and/or viroids.

Plants and plant varieties which can likewise be treated in accordancewith the invention are those plants which are resistant to one or moreabiotic stress factors. Abiotic stress conditions may include, forexample, drought, cold temperature exposure, heat exposure, osmoticstress, waterlogging, increased soil salinity, increased exposure tominerals, exposure to ozone, exposure to strong light, limitedavailability of nitrogen nutrients, limited availability of phosphorusnutrients or lack of shade.

Plants and plant varieties which can likewise be treated in accordancewith the invention are those plants characterized by enhanced yieldcharacteristics. Enhanced yield in said plants can be the result of, forexample, improved plant physiology, growth and development, such aswater use efficiency, water retention efficiency, improved nitrogen use,enhanced carbon assimilation, improved photosynthesis, increasedgermination efficiency and accelerated maturation. Yield can also beaffected by improved plant architecture (under stress and non-stressconditions), including early flowering, flowering control for hybridseed production, seedling vigour, plant size, internode number anddistance, root growth, seed size, fruit size, pod size, pod or earnumber, seed number per pod or ear, seed mass, enhanced seed filling,reduced seed dispersal, reduced pod dehiscence and lodging resistance.Further yield traits include seed composition, such as carbohydratecontent, protein content, oil content and composition, nutritionalvalue, reduction in anti-nutritional compounds, improved processabilityand better storage stability.

Plants which can be treated in accordance with the invention are hybridplants that already express the characteristics of heterosis, or hybridvigour, which results in generally higher yield, increased vigour,better health and better resistance towards biotic and abiotic stressfactors. Such plants are typically obtained by crossing an inbredmale-sterile parent line (the female parent) with another inbredmale-fertile parent line (the male parent). Hybrid seed is typicallyharvested from the male-sterile plants and sold to growers. Male-sterileplants can sometimes (for example in maize) be produced by detasseling(i.e. mechanical removal of the male reproductive organs or maleflowers); however, it is more typical for male sterility to be theresult of genetic determinants in the plant genome. In that case, andespecially when seed is the desired product to be harvested from thehybrid plants, it is typically favourable to ensure that male fertilityin hybrid plants which contain the genetic determinants responsible formale sterility is fully restored. This can be accomplished by ensuringthat the male parents have appropriate fertility restorer genes whichare capable of restoring the male fertility in hybrid plants thatcontain the genetic determinants responsible for male sterility. Geneticdeterminants for male sterility may be located in the cytoplasm.Examples of cytoplasmic male sterility (CMS) were for instance describedfor Brassica species. However, genetic determinants for male sterilitycan also be located in the nuclear genome. Male-sterile plants can alsobe obtained by plant biotechnology methods such as genetic engineering.A particularly useful means of obtaining male-sterile plants isdescribed in WO 89/10396 in which, for example, a ribonuclease such as abarnase is selectively expressed in the tapetum cells in the stamens.Fertility can then be restored by expression in the tapetum cells of aribonuclease inhibitor such as barstar.

Plants or plant varieties (obtained by plant biotechnology methods suchas genetic engineering) which may be treated in accordance with theinvention are herbicide-tolerant plants, i.e. plants made tolerant toone or more given herbicides. Such plants can be obtained either bygenetic transformation, or by selection of plants containing a mutationimparting such herbicide tolerance.

Herbicide-tolerant plants are for example glyphosate-tolerant plants,i.e. plants made tolerant to the herbicide glyphosate or salts thereof.For example, glyphosate-tolerant plants can be obtained by transformingthe plant with a gene encoding the enzyme5-enolpyruvylshikimate-3-phosphate synthase (EPSPS). Examples of suchEPSPS genes are the AroA gene (mutant CT7) of the bacterium Salmonellatyphimurium, the CP4 gene of the bacterium Agrobacterium sp., the genesencoding a petunia EPSPS, a tomato EPSPS, or an Eleusine EPSPS. It canalso be a mutated EPSPS. Glyphosate-tolerant plants can also be obtainedby expressing a gene that encodes a glyphosate oxidoreductase enzyme.Glyphosate-tolerant plants can also be obtained by expressing a genethat encodes a glyphosate acetyl transferase enzyme. Glyphosate-tolerantplants can also be obtained by selecting plants containingnaturally-occurring mutations of the abovementioned genes.

Other herbicide-resistant plants are for example plants which have beenmade tolerant to herbicides inhibiting the enzyme glutamine synthase,such as bialaphos, phosphinothricin or glufosinate. Such plants can beobtained by expressing an enzyme detoxifying the herbicide or a mutantglutamine synthase enzyme that is resistant to inhibition. One suchefficient detoxifying enzyme is, for example, an enzyme encoding aphosphinothricin acetyltransferase (such as the bar or pat protein fromStreptomyces species for example). Plants expressing an exogenousphosphinothricin acetyltransferase have been described.

Further herbicide-tolerant plants are also plants that have been madetolerant to the herbicides inhibiting the enzymehydroxyphenylpyruvatedioxygenase (HPPD).Hydroxyphenylpyruvatedioxygenases are enzymes that catalyse the reactionin which para-hydroxyphenylpyruvate (HPP) is transformed intohomogentisate. Plants tolerant to HPPD inhibitors can be transformedwith a gene encoding a naturally occurring resistant HPPD enzyme, or agene encoding a mutated HPPD enzyme. Tolerance to HPPD-inhibitors canalso be obtained by transforming plants with genes encoding certainenzymes enabling the formation of homogentisate despite the inhibitionof the native HPPD enzyme by the HPPD-inhibitor. Tolerance of plants toHPPD inhibitors can also be improved by transforming plants with a geneencoding an enzyme prephenate dehydrogenase in addition to a geneencoding an HPPD-tolerant enzyme.

Further herbicide-resistant plants are plants that have been madetolerant to acetolactate synthase (ALS) inhibitors. Known ALS inhibitorsinclude, for example, sulphonylurea, imidazolinone, triazolopyrimidines,pyrimidinyl oxy(thio)benzoates, and/orsulphonylaminocarbonyltriazolinone herbicides. Different mutations inthe ALS enzyme (also known as acetohydroxyacid synthase. AHAS) are knownto confer tolerance to different herbicides and groups of herbicides.The production of sulphonylurea-tolerant plants andimidazolinone-tolerant plants has been described in the internationalpublication WO 1996/033270. Further sulphonylurea- andimidazolinone-tolerant plants have also been described, for example inWO 2007/024782.

Other plants tolerant to imidazolinone and/or sulphonylurea can beobtained by induced mutagenesis, by selection in cell cultures in thepresence of the herbicide or by mutation breeding.

Plants or plant varieties (obtained by plant biotechnology methods suchas genetic engineering) which may also be treated in accordance with theinvention are insect-resistant transgenic plants, i.e. plants maderesistant to attack by certain target insects. Such plants can beobtained by genetic transformation, or by selection of plants containinga mutation imparting such insect resistance.

In the present context, the term “insect-resistant transgenic plant”includes any plant containing at least one transgene comprising a codingsequence encoding:

-   1) an insecticidal crystal protein from Bacillus thuringiensis or an    insecticidal portion thereof, such as the insecticidal crystal    proteins listed online at:    http://www.lifesci.sussex.ac.uk/Home/Neil_Crickmore/Bt/, or    insecticidal portions thereof, for example proteins of the Cry    protein classes Cry1Ab, Cry1Ac, Cry1F, Cry2Ab, Cry3Ae or Cry3Bb or    insecticidal portions thereof; or-   2) a crystal protein from Bacillus thuringiensis or a portion    thereof which is insecticidal in the presence of a second other    crystal protein from Bacillus thuringiensis or a portion thereof,    such as the binary toxin made up of the Cy34 and Cy35 crystal    proteins; or-   3) a hybrid insecticidal protein comprising parts of two different    insecticidal crystal proteins from Bacillus thuringiensis, such as a    hybrid of the proteins of 1) above or a hybrid of the proteins of 2)    above, for example the Cry1A.105 protein produced by maize event    MON98034 (WO 2007/027777); or-   4) a protein of any one of points 1) to 3) above wherein some,    particularly 1 to 10, amino acids have been replaced by another    amino acid to obtain a higher insecticidal activity to a target    insect species, and/or to expand the range of target insect species    affected, and/or because of changes induced in the encoding DNA    during cloning or transformation, such as the Cry3Bb1 protein in    maize events MON863 or MON88017, or the Cry3A protein in maize event    MIR 604:-   5) an insecticidal secreted protein from Bacillus thuringiensis or    Bacillus cereus, or an insecticidal portion thereof, such as the    vegetative insecticidal proteins (VIP) listed at:    http://www.lifesci.sussex.ac.uk/Home/Neil_Crickmore/Bt/vip.html, for    example proteins from the VIP3Aa protein class; or-   6) a secreted protein from Bacillus thuringiensis or Bacillus cereus    which is insecticidal in the presence of a second secreted protein    from Bacillus thuringiensis or B. cereus, such as the binary toxin    made up of the VIP1A and VIP2A proteins.-   7) a hybrid insecticidal protein comprising parts from different    secreted proteins from Bacillus thuringiensis or Bacillus cereus,    such as a hybrid of the proteins in 1) above or a hybrid of the    proteins in 2) above; or-   8) a protein of any one of points 1) to 3) above wherein some,    particularly 1 to 10, amino acids have been replaced by another    amino acid to obtain a higher insecticidal activity to a target    insect species, and/or to expand the range of target insect species    affected, and/or because of changes induced in the encoding DNA    during cloning or transformation (while still encoding an    insecticidal protein), such as the VIP3Aa protein in cotton event    COT 102.

Of course, insect-resistant transgenic plants, as used herein, alsoinclude any plant comprising a combination of genes encoding theproteins of any one of the above classes 1 to 8. In one embodiment, aninsect-resistant plant contains more than one transgene encoding aprotein of any one of the above classes 1 to 8, to expand the range oftarget insect species affected or to delay insect resistance developmentto the plants, by using different proteins insecticidal to the sametarget insect species but having a different mode of action, such asbinding to different receptor binding sites in the insect.

Plants or plant varieties (obtained by plant biotechnology methods suchas genetic engineering) which may also be treated in accordance with theinvention are tolerant to abiotic stress factors. Such plants can beobtained by genetic transformation, or by selection of plants containinga mutation imparting such stress resistance. Particularly usefulstress-tolerant plants include the following:

-   a. plants which contain a transgene capable of reducing the    expression and/or the activity of the poly(ADP-ribose)polymerase    (PARP) gene in the plant cells or plants;-   b. plants which contain a stress tolerance-enhancing transgene    capable of reducing the expression and/or the activity of the    PARG-encoding genes of the plants or plant cells;-   c. plants which contain a stress tolerance-enhancing transgene    coding for a plant-functional enzyme of the nicotinamide adenine    dinucleotide salvage biosynthesis pathway, including nicotinamidase,    nicotinate phosphoribosyltransferase, nicotinic acid mononucleotide    adenyltransferase, nicotinamide adenine dinucleotide synthetase or    nicotinamide phosphoribosyltransferase.

Plants or plant varieties (obtained by plant biotechnology methods suchas genetic engineering) which may also be treated in accordance with theinvention show altered quantity, quality and/or storage stability of theharvested product and/or altered properties of specific ingredients ofthe harvested product such as, for example:

-   1) Transgenic plants which synthesize a modified starch which is    altered with respect to its chemophysical traits, in particular the    amylose content or the amylose/amylopectin ratio, the degree of    branching, the average chain length, the distribution of the side    chains, the viscosity behaviour, the gel resistance, the grain size    and/or grain morphology of the starch in comparison to the    synthesized starch in wild-type plant cells or plants, such that    this modified starch is better suited for certain applications.-   2) Transgenic plants which synthesize non-starch carbohydrate    polymers or which synthesize non-starch carbohydrate polymers with    altered properties in comparison to wild-type plants without genetic    modification. Examples are plants which produce polyfructose,    especially of the inulin and levan type, plants which produce    alpha-1,4-glucans, plants which produce alpha-1,6-branched    alpha-1,4-glucans, and plants producing alternan.-   3) Transgenic plants which produce hyaluronan.

Plants or plant varieties (obtained by plant biotechnology methods suchas genetic engineering) which may also be treated in accordance with theinvention are plants, such as cotton plants, with altered fibrecharacteristics. Such plants can be obtained by genetic transformation,or by selection of plants containing a mutation imparting such alteredfibre characteristics and include:

-   a) plants, such as cotton plants, which contain an altered form of    cellulose synthase genes;-   b) plants, such as cotton plants, which contain an altered form of    rsw2 or rsw3 homologous nucleic acids;-   c) plants, such as cotton plants, with an increased expression of    sucrose phosphate synthase;-   d) plants, such as cotton plants, with an increased expression of    sucrose synthase;-   e) plants, such as cotton plants, wherein the timing of the    plasmodesmatal gating at the basis of the fibre cell is altered, for    example through downregulation of fibre-selective β-1,3-glucanase;-   f) plants, such as cotton plants, which have fibres with altered    reactivity, for example through the expression of the    N-acetylglucosaminetransferase gene including nodC and chitin    synthase genes.

Plants or plant cultivars (obtained by plant biotechnology methods suchas genetic engineering) which may also be treated in accordance with theinvention are plants, such as oilseed rape or related Brassica plants,with altered oil profile characteristics. Such plants can be obtained bygenetic transformation or by selection of plants containing a mutationimparting such altered oil characteristics and include:

-   a) plants, such as oilseed rape plants, which produce oil having a    high oleic acid content;-   b) plants, such as oilseed rape plants, which produce oil having a    low linolenic acid content;-   c) plants, such as oilseed rape plants, which produce oil having a    low level of saturated fatty acids.

Particularly useful transgenic plants which may be treated in accordancewith the invention are plants which comprise one or more genes whichencode one or more toxins and are the transgenic plants available underthe following trade names: YIELD GARD® (for example maize, cotton, soyabeans), KnockOut® (for example maize), BiteGard® (for example maize),BT-Xtra® (for example maize), StarLink® (for example maize), Bollgard®(cotton), Nucotn® (cotton), Nucotn 33B® (cotton), NatureGard® (forexample maize). Protecta® and NewLeafM (potato). Examples ofherbicide-tolerant plants which may be mentioned are maize varieties,cotton varieties and soya bean varieties which are available under thefollowing trade names: Roundup Ready® (tolerance to glyphosate, forexample maize, cotton, soya beans), Liberty Link® (tolerance tophosphinothricin, for example oilseed rape), IMI® (tolerance toimidazolinone) and SCS® (tolerance to sulphonylurea, for example maize).Herbicide-resistant plants (plants bred in a conventional manner forherbicide tolerance) which may be mentioned include the varieties soldunder the name Clearfield® (for example maize).

Particularly useful transgenic plants which may be treated in accordancewith the invention are plants containing transformation events, or acombination of transformation events, and that are listed for example inthe databases for various national or regional regulatory agencies (seefor example http://gmoinfo.jrc.it/gmp_browsc.aspx andhttp://www.agbios.com/dbase.php).

The plants listed can be treated in accordance with the invention in aparticularly advantageous manner with the compounds of the generalformula (I) and/or the inventive active ingredient mixtures. Thepreferred ranges stated above for the active ingredients or mixturesalso apply to the treatment of these plants. Particular emphasis isgiven to the treatment of plants with the compounds or mixturesspecifically mentioned in the present text.

The inventive active ingredients or compositions can thus be used toprotect plants from attack by the pathogens mentioned for a certainperiod after treatment. The period for which protection is providedgenerally lasts for 1 to 28 days, preferably for 1 to 14 days, morepreferably for 1 to 10 days, most preferably for 1 to 7 days after thetreatment of the plants with the active ingredients, or for up to 200days after a seed treatment.

The preparation and the use of the inventive active ingredients of theformula (I) are illustrated by the examples which follow. However, theinvention is not limited to these examples.

General Note:

Unless stated otherwise, all chromatographic purification and separationsteps were carried out on silica gel and with a solvent gradient of0:100 ethyl acetate/cyclohexane to 100:0 ethyl acetate/hexane.

Preparation of Compounds of the Formula (I)

2-[3,5-Bis(difluoromethyl)-1H-pyrazol-yl]-1-{4-fluoro-4-[4-(5-phenyl-4,5-dihydro-1,2-oxazol-3-yl)-1,3-thiazol-2-yl]piperidin-1-yl}ethanone(I-5)

Process A

tert-Butyl4-(4-bromo-1,3-thiazol-2-yl)-4-hydroxypiperidine-1-carboxylate (IV-1)

To a solution of 2,4-dibromo-1,3-thiazole (8.8 g) in dichloromethane(180 ml) was added dropwise, at −78° C., under argon, n-butyllithium(1.6 M in tetrahydrofuran, 25 ml). The reaction mixture was stirred at−78° C., for 20 minutes and then tert-butyl4-oxopiperidine-1-carboxylate was added. The mixture was stirred at roomtemperature for 30 minutes. The reaction mixture was subsequentlyadmixed with saturated ammonium chloride solution at −30° C., and theaqueous phase was removed. After the aqueous phase had been extractedwith dichloromethane, the combined organic phases were dried over sodiumsulphate and concentrated under reduced pressure. The residue waspurified by chromatography. This gave tert-butyl4-(4-bromo-1,3-thiazol-2-yl)-4-hydroxypiperidine-1-carboxylate (15.3 g).

¹H NMR (DMSO-d₆): δ_(ppm): 1.43 (s, 9H), 1.70 (d, 2H), 1.88 (ddd, 2H),3.11 (bs, 2H), 3.83 (d, 2H), 6.31 (s, 1H), 7.72 (s, 1H)

log P (HCOOH): 2.74

MS (ESI): 363 and 365 ([M+H]⁺)

Process B

tert-Butyl 4-(4-bromo-1,3-thiazol-2-yl)-4-fluoropiperidine-1-carboxylate(V-1)

tert-Butyl4-(4-bromo-1,3-thiazol-2-yl)-4-hydroxypiperidine-1-carboxylate (17.7 g)was initially charged under argon at 0° C. in dichloromethane in a PEflask, and diethylaminosulphur trifluoride (DAST) (7.08 ml) was addeddropwise. The cooling was removed. After stirring overnight, saturatedaqueous sodium hydrogencarbonate solution was added and the mixture wasextracted with dichloromethane. The organic extracts were dried oversodium sulphate and concentrated under reduced pressure. The residue waspurified by chromatography. This gave tert-butyl4-(4-bromo-1,3-thiazol-2-yl)-4-fluoropiperidine-1-carboxylate (18.0 g).

¹H NMR (DMSO-d₆): δ_(ppm): 1.42 (s, 9H), 2.13-2.00 (m, 4H), 3.14 (bs,2H), 3.95-3.87 (m, 2H), 7.95 (s, 1H)

log P (HCOOH): 3.94

MS (ESI): 309 and 311 ([M-C(CH₃)₃+2H]⁺)

Process C

tert-Butyl4-fluoro-4-(4-formyl-1,3-thiazol-2-yl)piperidine-1-carboxylate (VI-1)

To a solution of tert-butyl4-(4-bromo-1,3-thiazol-2-yl)-4-fluoropiperidine-1-carboxylate (245 mg)in dichloromethane (5 ml) was added dropwise, at −78° C., n-butyllithium(1.6 M in tetrahydrofuran, 0.42 ml). After 20 min, N,N-dimethylfomamide(0.16 ml) was added dropwise. After stirring at −78° C., for 30 minutes,saturated ammonium chloride solution was added, and the mixture wasextracted with dichloromethane. The organic extracts were dried oversodium sulphate and concentrated under reduced pressure. The residue waspurified by chromatography. This gave tert-butyl4-fluoro-4-(4-formyl-1,3-thiazol-2-yl)piperidine-1-carboxylate (75 mg).

¹H NMR (DMSO-d₆): δ_(ppm): 1.43 (s, 9H), 2.18-2.04 (m, 4H), 3.17 (bs,2H), 3.97-3.89 (m, 2H), 8.80 (s, 1H), 9.92 (s, 1H)

log P (HCOOH): 2.80

MS (ESI): 259 ([M-C(CH₃)₃+2H]⁺)

Processes D and E

tert-Butyl4-fluoro-{4-[(E/Z)-(hydroxyimino)methyl]-1,3-thiazol-2-yl}piperidine-1-carboxylate

To a solution of tert-butyl4-fluoro-4-(4-formyl-1,3-thiazol-2-yl)piperidine-1-carboxylate (3.49 g)in ethanol (50 ml) was added dropwise hydroxylamine (50% in water, 0.81ml) at room temperature. The reaction mixture was stirred at 60° C., for1 hour, then the solvent was removed under reduced pressure. This gavetert-butyl4-fluoro-4-{4-[(E/Z)-(hydroxyimino)methyl]-1,3-thiazol-2-yl}piperidine-1-carboxylate(3.49 g).

¹H NMR (DMSO-d₆): δ_(ppm): 1.42 (s, 9H), 2.17-2.03 (m, 4H), 3.16 (bs,2H), 3.94-3.86 (m, 2H), 7.96 (s, 1H), 8.17 (s, 1H)

log P (HCOOH): 2.53

MS (ESI): 230 ([M-COOC(CH₃)₃+2H]⁺)

tert-Butyl4-fluoro-4-[4-(5-phenyl-4,5-dihydro-1,2-oxazol-3-yl)-1,3-thiazol-2-yl]piperidine-1-carboxylate(X-a-1)

To a solution of tert-butyl4-fluor-4-{4-[(E/Z)-(hydroxyimino)methyl]-1,3-thiazol-2-yl}piperidine-1-carboxylate(500 mg) in tetrahydrofuran (5 ml) was added dropwise, at roomtemperature, styrene (0.21 ml), followed by hypochlorite (13% in water).After stirring at room temperature for 4 hours, the solvent was removedunder reduced pressure. The residue was admixed with dichloromethane andwater, and extracted with dichloromethane. The organic extracts weredried over sodium sulphate and concentrated under reduced pressure. Theresidue was purified by chromatography. This gave tert-butyl4-fluoro-4-[4-(5-phenyl-4,5-dihydro-1,2-oxazol-3-yl)-1,3-thiazol-2-yl]piperidine-1-carboxylate(380 mg).

¹H NMR (DMSO-d₆): δ_(ppm): 1.42 (s, 9H), 2.14-2.07 (m, 4H), 3.15 (bs,2H), 3.38 (dd, 1H), 3.89 (dd, 1H), 3.93 (bs, 2H), 5.75 (dd, 1H), 7.34(m, 1H), 7.42-7.39 (m, 4H), 8.21 (s, 1H)

log P (HCOOH): 4.28

MS (ESI): 332 ([M-COOC(CH₃)₃+2H]⁺)

Process G

4-Fluoro-4-[4-(5-phenyl-4,5-dihydro-1,2-oxazol-3-yl)-1,3-thiazol-2-yl]piperidiniumchloride (XII-1)

To a solution of tert-butyl4-fluoro-4-[4-(5-phenyl-4,5-dihydro-1,2-oxazol-3-yl)-1,3-thiazol-2-yl]piperidine-1-carboxylate(380 mg) was added dropwise, at 0° C., a 4 molar solution ofhydrochloric acid in 1,4-dioxane. The reaction mixture was stirred at 0°C., and then gradually warmed to room temperature. After stirringovernight, the solvent and excess hydrogen chloride were removed. Thisgave4-fluoro-4-[4-(5-phenyl-4,5-dihydro-1,2-oxazol-3-yl)-1,3-thiazol-2-yl]piperidiniumchloride (374 mg).

¹H NMR (DMSO-d₆): δ_(ppm): 2.58-2.30 (m, 4H), 3.23-3.14 (m, 2H), 3.38(dd, 1H), 3.56 (s, 2H), 3.90 (dd, 1H), 5.76 (dd, 1H), 7.42-7.33 (m, 5H),8.25 (s, 1H), 9.08 (bs, 1H), 9.24 (bs, 1H)

log P (HCOOH): 1.17

MS (ESI): 332 ([M-Cl]⁺)

Process H

2-[3,5-Bis(difluoromethyl)-1H-pyrazol-1-yl]-1-{4-fluoro-4-[4-(5-phenyl-4,5-dihydro-1,2-oxazol-3-yl)-1,3-thiazol-2-yl]piperidin-1-yl}ethanone(I-5)

To a solution of [3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]acetic acid(230 mg) in dichloromethane (5 ml) were added oxalyl chloride (387 mg)and one drop of N,N-dimethylfomamide. The reaction mixture was stirredat room temperature overnight. After removing the solvent under reducedpressure, the residue was then dissolved in dichloromethane (5 ml), anda solution of4-fluoro-4-[4-(5-phenyl-4,5-dihydro-1,2-oxazol-3-yl)-1,3-thiazol-2-yl]piperidiniumchloride (374 mg) and of Hünig's base (394 mg) in dichloromethane (5 ml)was added dropwise at 0° C. The reaction mixture was stirred at roomtemperature for 3 hours. After addition of conc. ammonium chloridesolution, the aqueous phase was removed and extracted with ethylacetate. The combined organic phases were dried over sodium sulphate andconcentrated under reduced pressure. The residue was purified bychromatography. This gave2-[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]-1-{4-fluoro-4-[4-(5-phenyl-4,5-dihydro-1,2-oxazol-3-yl)-1,3-thiazol-2-yl]piperidin-1-yl}ethanone(250 mg).

¹H NMR (DMSO-d₆): δ_(ppm): 2.45-2.05 (m, 4H), 3.11 (m, 1H), 3.38 (dd,1H), 3.48 (m, 1H), 3.95-3.86 (m, 2H), 4.26 (m, 1H), 5.39 (d, 1H), 5.50(d, 1H), 5.76 (dd, 1H), 6.91 (s, 1H), 7.03 (t, 1H), 7.18 (t, 1H),7.42-7.33 (m, 5H), 8.22 (s, 1H)

log P (HCOOH): 3.41

MS (ESI): 540 ([M+H]⁺)

1-(4-{4-[5-(2-acetylphenyl)-4,5-dihydro-1,2-oxazol-3-yl]-1,3-thiazol-2-yl}piperidin-1-yl)-2-[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]ethanone(I-7)

Processes D and E

tert-Butyl4-(4-[5-(2-acetylphenyl)-4,5-dihydro-1,2-oxazol-3-yl]-1,3-thiazol-2-yl)piperidine-1-carboxylate(X-a-2)

To a solution of tert-butyl4-{4-[(Z/E)-(hydroxyimino)methyl]-1,3-thiazol-2-yl}piperidine-1-carboxylate(4.5 g) and 1-(2-vinylphenyl)ethanone (2.32 g) in ethyl acetate (70 ml)were added, at room temperature, potassium hydrogencarbonate (7.23 g)and N-chlorosuccinimide (2.31 g), and then three drops of water. Thereaction mixture was stirred at 60° C., for 3 hours, then admixed withethyl acetate and water and extracted with ethyl acetate. The organicextracts were dried over sodium sulphate and concentrated under reducedpressure. The residue was purified by chromatography. This gavetert-butyl4-{4-[5-(2-acetylphenyl)-4,5-dihydro-1,2-oxazol-3-yl]-1,3-thiazol-2-yl}piperidine-1-carboxylate(4.64 g).

¹H NMR (DMSO-d₆): δ_(ppm): 1.41 (s, 9H), 1.60-1.48 (m, 2H), 2.04-1.98(m, 2H), 2.63 (s, 3H), 2.89 (bs, 2H), 3.13 (dd, 1H), 3.27-3.18 (m, 1H),4.07-3.95 (m, 3H), 6.12 (dd, 1H), 7.48 (dd, 1H), 7.56 (d, 1H), 7.61 (dd,1H), 7.98 (s, 1H), 8.00 (d, 1H)

Process G

1-(2-{3-[2-(Piperidin-4-yl)-1,3-thiazol-4-yl]-4,5-dihydro-1,2-oxazol-5-yl}phenyl)ethanonehydrochloride (XII-2)

To a solution of tert-butyl4-{4-[5-(2-acetylphenyl)-4,5-dihydro-1,2-oxazol-3-yl]-1,3-thiazol-2-yl}piperidine-1-carboxylate(500 mg) in 1,4-dioxane (5 ml) was added dropwise, at 0° C., a 4 molarsolution of hydrogen chloride in 1,4-dioxane (4.2 ml). The reactionmixture was stirred at 0° C. and then gradually warmed to roomtemperature. After stirring overnight, the solvent and excess hydrogenchloride were removed. This gave1-(2-{3-[2-(piperidin-4-yl)-1,3-thiazol-4-yl]-4,5-dihydro-1,2-oxazol-5-yl}phenyl)ethanonehydrochloride (430 mg).

¹H NMR (DMSO-d₆): δ_(ppm): 1.99-1.85 (m, 2H), 2.23-2.15 (m, 2H), 2.63(s, 3H), 3.08-2.97 (m, 2H), 3.14 (dd, 1H), 3.43-3.30 (m, 3H), 4.00 (dd,1H), 6.12 (dd, 1H), 7.98 (dd, 1H), 7.56 (d, 1H), 7.62 (dd, 1H), 8.00 (d,1H), 8.03 (s, 1H), 8.75 (bs, 1H), 9.03 (bs, 1H)

log P (HCOOH): 0.96

MS (ESI): 358 ([M-Cl]⁺)

Process H

1-(4-{4-[5-(2-Acetylphenyl)-4,5-dihydro-1,2-oxazol-3-yl]-1,3-thiazol-2-yl}piperidin-1-yl)-2-[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]ethanone(I-7)

Solution A:

To a solution of [3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]acetic acid(280 mg) in dichloromethane (10 ml) were added dropwise, at roomtemperature, one drop of N,N-dimethylformamide and oxalyl chloride(0.295 ml). After stirring at room temperature for two hours, thesolvent was removed and the residue was dissolved again indichloromethane (10 ml) (solution A).

To a solution of1-(2-{3-[2-(piperidin-4-yl)-1,3-thiazol-4-yl]-4,5-dihydro-1,2-oxazol-5-yl}phenyl)ethanonehydrochloride (441 mg) in dichloromethane (5 ml) was added, at roomtemperature, diisopropylethylamine (588 ml). After 15 minutes, solutionA was added dropwise. After stirring at room temperature overnight, thereaction mixture was admixed with water and extracted with ethylacetate. The organic extracts were dried over sodium sulphate andconcentrated under reduced pressure. The residue was purified bychromatography. This gave1-(4-{4-[5-(2-acetylphenyl)-4,5-dihydro-1,2-oxazol-3-yl]-1,3-thiazol-2-yl}piperidin-1-yl)-2-[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]ethanone(590 mg).

2-{3-[2-(1-{[3,5-Bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazol-4-yl]-4,5-dihydro-1,2-oxazol-5-yl}benzaldehyde(I-26)

Processes D and E

tert-Butyl4-(4-[5-(2-formylphenyl)-4,5-dihydro-1,2-oxazol-3-yl]-1,3-thiazol-2-yl)piperidine-1-carboxylate(X-a-3) tert-Butyl4-{4-[(Z/E)-(hydroximino)methyl]-1,3-thiazol-2-yl}piperidine-1-carboxylate(5.6 g) and 2-vinylbenzaldehyde (2.61 g) were reacted analogously to I-7(Processes D and E). This gave tert-butyl4-{4-[5-(2-formylphenyl)-4,5-dihydro-1,2-oxazol-3-yl]-1,3-thiazol-2-yl}piperidine-1-carboxylate(5.69 g).

¹H NMR (DMSO-d₆): δ_(ppm): 1.41 (s, 9H), 1.60-1.48 (m, 2H), 2.04-1.98(m, 2H), 2.89 (bs, 2H), 3.28-3.15 (m, 2H), 4.07-3.95 (m, 3H), 6.42 (dd,1H), 7.64-7.57 (m, 2H), 7.72 (dd, 1H), 7.99 (s, 1H), 8.03 (d, 1H), 10.18(s, 1H)

log P (HCOOH): 3.76

MS (ESI): 342 ([M-COOC(CH₃)₃+2H]⁺)

Process G

2-{3-[2-(Piperidin-4-yl)-1,3-thiazol-4-yl]-4,5-dihydro-1,2-oxazol-5-yl}benzaldehydehydrochloride (XII-3)

tert-Butyl4-{4-[5-(2-formylphenyl)-4,5-dihydro-1,2-oxazol-3-yl]-1,3-thiazol-2-yl}piperidine-1-carboxylate(5.1 g) was reacted analogously to I-7 (Process G). This gave2-{3-[2-(piperidin-4-yl)-1,3-thiazol-4-yl]-4,5-dihydro-1,2-oxazol-5-yl}benzaldehydehydrochloride (4.35 g).

¹H NMR (DMSO-d₆): δ_(ppm): 2.02-1.89 (m, 2H), 2.23-2.15 (m, 2H),3.08-2.97 (m, 2H), 3.18 (dd, 1H), 3.35-3.29 (m, 2H), 3.41-3.35 (m, 1H),4.05 (dd, 1H), 6.42 (dd, 1H), 7.64-7.57 (m, 2H), 7.72 (dd, 1H), 8.02 (d,1H), 8.03 (s, 1H), 10.19 (s, 1H)

log P (HCOOH): 0.76

MS (ESI): 342 ([M-Cl]⁺)

Process H

2-({3-[2-(1-{[3,5-Bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazol-4-yl]-4,5-dihydro-1,2-oxazol-5-yl}benzaldehyde(I-26)

2-{3-[2-(Piperidin-4-yl)-1,3-thiazol-4-yl]-4,5-dihydro-1,2-oxazol-5-yl}benzaldehydehydrochloride (432 mg) was reacted analogously to I-7 (Process G). Thisgave2-{3-[2-(1-{[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazol-4-yl]-4,5-dihydro-1,2-oxazol-5-yl}benzaldehyde(330 mg).

2-[3,5-Bis(difluoromethyl)-1H-pyrazol-1-yl]-1-(4-{4-[5-(2-ethynylphenyl)-4,5-dihydro-1,2-oxazol-3-yl]-1,3-thiazol-2-yl}piperidin-1-yl)ethanone(I-38)

To a solution of 4-acetamidobenzenesulphonyl azide (140 mg) inacetonitrile (10 ml) was added, at room temperature, dimethyl2-oxopropylphosphonate (97 mg). After stirring for 2 hours,2-{3-[2-(1-{[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazol-4-yl]-4,5-dihydro-1,2-oxazol-5-yl}benzaldehyde(267 mg) in methanol (2 ml) was added to the reaction mixture. Afterstirring for 8 hours, the reaction mixture was admixed with ethylacetate and water and extracted with ethyl acetate. The organic extractswere dried over sodium sulphate and concentrated under reduced pressure.The residue was purified by chromatography. This gavetert-2-[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]-1-(4-{4-[5-(2-ethynylphenyl)-4,5-dihydro-1,2-oxazol-3-yl]-1,3-thiazol-2-yl}piperidin-1-yl)ethanone(50 mg).

N-(2-{3-[2-(1-{[3,5-Bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazol-4-yl]-4,5-dihydro-1,2-oxazol-5-yl}phenyl)methanesulphonamide(I-37)

Processes D and E

tert-Butyl4-[4-(5-{2-[(methylsulphonyl)amino]phenyl}-4,5-dihydro-1,2-oxazol-3-yl)-1,3-thiazol-2-yl]piperidine-1-carboxylate(X-a-4)

tert-Butyl4-{4-[(Z/E)-(hydroxyimino)methyl]-1,3-thiazol-2-yl}piperidine-1-carboxylate(1.35 g) and N-(2-vinylphenyl)methanesulphonamide (1.11 g) were reactedanalogously to I-7 (Processes D and E). This gave tert-butyl4-[4-(5-{2-[(methylsulphonyl)amino]phenyl}-4,5-dihydro-1,2-oxazol-3-yl)-1,3-thiazol-2-yl]piperidine-1-carboxylate(0.94 g).

¹H NMR (DMSO-d₆): δ_(ppm) 1.41 (s, 9H), 1.51-1.49 (m, 2H), 2.08-2.00 (m,2H), 2.95-2.84 (m, 2H), 3.03 (s, 3H), 3.38-3.21 (m, 2H), 3.90 (dd, 1H),4.05-3.96 (m, 2H), 6.09 (dd, 1H), 7.43-7.30 (m, 4H), 8.00 (s, 1H), 9.18(bs, 1H)

log P (HCOOH): 3.00

MS (ESI): 407 ([M-COOC(CH₃)₃+2H]⁺)

Process G

4-[4-(5-{2-[(Methylsulphonyl)amino]phenyl}-4,5-dihydro-1,2-oxazol-3-yl)-1,3-thiazol-2-yl]piperidiniumchloride (XII-4)

tert-Butyl4-[4-(5-{2-[(methylsulphonyl)amino]phenyl}-4,5-dihydro-1,2-oxazol-3-yl)-1,3-thiazol-2-yl]piperidine-1-carboxylate(900 ing) was reacted analogously to I-7 (Process G). This gave4-[4-(5-{2-[(methylsulphonyl)amino]phenyl}-4,5-dihydro-1,2-oxazol-3-yl)-1,3-thiazol-2-yl]piperidiniumchloride (1.00 g),

log P (HCOOH): 0.72

MS (ESI): 407 ([M-Cl+2H]⁺)

Process H

N-(2-{3-[2-(1-{[3,5-Bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazol-4-yl]4,5-dihydro-1,2-oxazol-5-yl}phenyl)methanesulphonamide(I-37)

4-[4-(5-{2-[(Methylsulphonyl)amino]phenyl}-4,5-dihydro-1,2-oxazol-3-yl)-1,3-thiazol-2-yl]piperidiniumchloride (299 mg) was reacted analogously to I-7 (Process G). This gaveN-(2-{3-[2-(1-{[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazol-4-yl]-4,5-dihydro-1,2-oxazol-5-yl}phenyl)methanesulphonamide(215 mg).

2-[3,5-Bis(difluoromethyl)-1H-pyrazol-1-yl]-1-(4-{4-[5-(2-hydroxyphenyl)-4,5-dihydro-1,2-oxazol-3-yl]-1,3-thiazol-2-yl}piperidin-1-yl)ethanone(I-9)

Processes D and E

tert-Butyl4-{4-[5-(2-hydroxyphenyl)-4,5-dihydro-1,2-oxazol-3-yl]-1,3-thiazol-2-yl}piperidine-1-carboxylate(X-a-5)

To a solution of tert-butyl4-{4-[(hydroxyimino)methyl]-1,3-thiazol-2-yl}piperidine-1-carboxylate(3.46 g) and 2-vinylphenol (1.60 g) in ethyl acetate (50 ml) were added,at room temperature, potassium hydrogencarbonate (5.55 g) andN-chlorosuccinimide (1.78 g), and then one drop of water.

After stirring at 60° C., overnight, the reaction mixture was admixedwith ethyl acetate and water and extracted with ethyl acetate. Theorganic extracts were dried over sodium sulphate and concentrated underreduced pressure. The residue was purified by chromatography. This gavetert-butyl4-{4-[5-(2-hydroxyphenyl)-4,5-dihydro-1,2-oxazol-3-yl]-1,3-thiazol-2-yl}piperidine-1-carboxylate(1.70 g).

¹H NMR (DMSO-d₆, 400 MHz): δ_(ppm): 1.41 (s, 9H), 1.49-1.61 (m, 2H),1.98-2.06 (m, 2H), 2.82-2.96 (m, 2H), 3.80 (dd, 1H), 3.96-4.05 (m, 2H),5.82 (dd, 1H), 6.79 (t, 1H), 6.85 (d, 1H), 7.13 (t, 1H), 7.20 (d, 1H),7.98 (s, 1H), 9.70 (s, 1H)

log P (pH2.7): 3.22

MS (ESI): 330 ([M+H-C₄H₉OCO]⁺)

Process G

4-{4-[5-(2-Hydroxyphenyl)-4,5-dihydro-1,2-oxazol-3-yl]-1,3-thiazol-2-yl}piperidiniumchloride (XII-5)

To a solution of tert-butyl4-{4-[5-(2-hydroxyphenyl)-4,5-dihydro-1,2-oxazol-3-yl]-1,3-thiazol-2-yl}piperidine-1-carboxylate(1.70 g) in dichloromethane was added dropwise, at 0° C., a 4 molarsolution of hydrogen chloride (4.0 eq.) in 1,4-dioxane. The reactionmixture was stirred at 0° C., and then gradually warmed to roomtemperature. After stirring overnight, the solvent and excess hydrogenchloride were removed. This gave4-{4-[5-(2-hydroxy-phenyl)-4,5-dihydro-1,2-oxazol-3-yl]-1,3-thiazol-2-yl}piperidiniumchloride (1.45 g).

¹H NMR (DMSO-d₆, 400 MHz): δ_(ppm): 1.85-1.98 (m, 2H), 2.15-2.23 (m,2H), 2.98-3.09 (m, 2H), 3.26 (dd, 1H), 3.81 (dd, 1H), 5.83 (dd, 1H),6.79 (t, 1H), 6.86 (d, 1H), 7.13 (t, 1H), 7.20 (d, 1H), 8.02 (s, 1H),8.58 (bs, 1H), 8.87 (bs, 1H), 9.74 (s, 1H)

log P (pH2.7): 0.69

MS (ESI): 330 ([M+H]⁺)

Process H

2-[3,5-Bis(difluoromethyl)-1H-pyrazol-1-yl]-1-(4-{4-[5-(2-hydroxyphenyl)-4,5-dihydro-1,2-oxazol-3-yl]-1,3-thiazol-2-yl}piperidin-1-yl)ethanone(I-9)

To a solution of [3,5-bis-(difluoromethyl)-1H-pyrazol-1-yl]acetic acid(982 mg) in dichloromethane (10 ml) are added, at 0° C., oxalyl chloride(1.50 g) and one drop of N,N-dimethylformamide. The reaction mixture isstirred at room temperature for 60 minutes. The solvent and the excessreagent are removed under reduced pressure. The solid residue isdissolved again in dichloromethane and added dropwise at 0° C., to asolution of4-{4-[5-(2-hydroxyphenyl)-4,5-dihydro-1,2-oxazol-3-yl]-1,3-thiazol-2-yl}piperidiniumchloride (1.45 g) and triethylamine (5.5 ml) in dichloromethane (14 ml).The reaction mixture is stirred at room temperature for 3 h. Then it isadmixed with concentrated sodium hydrogencarbonate solution, and theaqueous phase is removed and extracted with ethyl acetate. The combinedorganic phases are dried over sodium sulphate and concentrated.Purification by column chromatography gives2-[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]-1-(4-{4-[5-(2-hydroxyphenyl)-4,5-dihydro-1,2-oxazol-3-yl]-1,3-thiazol-2-yl}piperidin-1-yl)ethanone(900 mg).

2-[3,5-Bis(difluoromethyl)-1H-pyrazol-1-yl]-1-[4-(4-{5-[2-(prop-2-yn-1-yloxy)phenyl]-4,5-dihydro-1,2-oxazol-3-yl}-1,3-thiazol-2-yl)piperidin-1-yl]ethanone(I-21)

To a solution of2-[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]-1-(4-{4-[5-(2-hydroxyphenyl)-4,5-dihydro-1,2-oxazol-3-yl]-1,3-thiazol-2-yl}piperidin-1-yl)ethanone(60 mg) and potassium carbonate (23 mg) in DMF (3 ml) are added, at roomtemperature, potassium iodide (10 mg) and 3-bromoprop-1-yne (21 mg). Thereaction mixture is stirred at 80° C., for 9 h. Then the mixture isadmixed with dilute hydrochloric acid and extracted with ethyl acetate.The combined organic phases are dried over sodium sulphate andconcentrated. Purification by column chromatography gives2-[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]-1-[4-(4-{5-[2-(prop-2-yn-1-yloxy)phenyl]-4,5-dihydro-1,2-oxazol-3-yl}-1,3-thiazol-2-yl)piperidin-1-yl]ethanone(40 mg).

2-{3-[2-(1-{[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazol-4-yl]-4,5-dihydro-1,2-oxazol-5-yl}phenylcyclohexanecarboxylate (I-32)

To a solution of2-[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]-1-(4-{4-[5-(2-hydroxyphenyl)-4,5-dihydro-1,2-oxazol-3-yl]-1,3-thiazol-2-yl}piperidin-1-yl)ethanone(150 mg) and triethylamine (33 mg) in methylene chloride (10 ml) isadded, at 0° C., a solution of cyclohexanecarbonyl chloride in methylenechloride (2 ml). The ice bath is removed and the reaction mixture isstirred at 0° C.—RT for 3 h. Then the mixture is admixed with dilutesodium hydrogencarbonate solution and extracted with methylene chloride.The combined organic phases are dried over sodium sulphate andconcentrated. Purification by column chromatography gives2-{3-[2-(1-{[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazol-4-yl]-4,5-dihydro-1,2-oxazol-5-ylphenyl cyclohexanecarboxylate (150 mg).

2-[3,5-Bis(difluoromethyl)-1H-pyrazol-1-yl]-1-(4-{4-[5-(2-nitrophenyl)-4,5-dihydro-1,2-oxazol-3-yl]-1,3-thiazol-2-yl}piperidin-1-yl)ethanone(I-10)

Processes D and E

tert-Butyl4-{4-[5-(2-nitrophenyl)-4,5-dihydro-1,2-oxazol-3-yl]-1,3-thiazol-2-yl}piperidine-1-carboxylate(X-a-6)

To a solution of tert-butyl4-{4-[(hydroxyimino)methyl]-1,3-thiazol-2-yl}piperidine-1-carboxylate(2.80 g) and 1-nitro-2-vinylbenzene (1.60 g) in ethyl acetate (50 ml)were added, at room temperature, potassium hydrogencarbonate (4.50 g)and N-chlorosuccinimide (1.44 g) and then one drop of water. Afterstirring at 60° C., overnight, the reaction mixture was admixed withethyl acetate and water and extracted with ethyl acetate. The organicextracts were dried over sodium sulphate and concentrated under reducedpressure. The residue was purified by chromatography. This gavetert-butyl4-{4-[5-(2-nitrophenyl)-4,5-dihydro-1,2-oxazol-3-yl]-1,3-thiazol-2-yl}piperidine-1-carboxylate(2.10 g).

¹H NMR (DMSO-d₆, 400 MHz): δ_(ppm): 1.40 (s, 9H), 1.48-1.60 (m, 2H),1.98-2.06 (m, 2H), 2.81-2.96 (m, 2H), 3.40 (dd, 1H), 3.96-4.04 (m, 2H),4.09 (dd, 1H), 6.24 (dd, 1H), 7.64 (t, 1H), 7.66 (d, 1H), 7.79 (t, 1H),8.02 (s, 1H), 8.15 (d, 1H)

log P (pH2.7): 4.01

MS (ESI): 359 ([M+H-C₄H₉OCO]⁺)

Process G

4-{4-[5-(2-Nitrophenyl)-4,5-dihydro-1,2-oxazol-3-yl]-1,3-thiazol-2-yl}piperidiniumchloride (XII-6)

To a solution of tert-butyl4-{4-[5-(2-nitrophenyl)-4,5-dihydro-1,2-oxazol-3-yl]-1,3-thiazol-2-yl}piperidine-1-carboxylate(2.10 g) in dichloromethane was added dropwise, at 0° C., a 4 molarsolution of hydrogen chloride (4.0 eq.) in 1,4-dioxane. The reactionmixture was stirred at 0° C. and then gradually warmed to roomtemperature. After stirring overnight, the solvent and excess hydrogenchloride were removed. This gave4-{4-[5-(2-nitrophenyl)-4,5-dihydro-1,2-oxazol-3-yl]-1,3-thiazol-2-yl}piperidiniumchloride (1.60 g).

¹H NMR (DMSO-d₆, 400 MHz): δ_(ppm): 1.86-1.97 (m, 2H), 2.15-2.23 (m,2H), 2.98-3.09 (m, 2H), 4.10 (dd, 1H), 6.24 (dd, 1H), 7.62 (t, 1H), 7.67(d, 1H), 7.81 (t, 1H), 8.07 (s, 1H), 8.16 (d, 1H), 8.63 (bs, 1H), 8.91(bs, 1H)

log P (pH2.7): 1.09

MS (ESI): 359 ([M+H]⁺)

Process H

2-[3,5-Bis(difluoromethyl)-1H-pyrazol-1-yl]-1-(4-{4-[5-(2-nitrophenyl)-4,5-dihydro-1,2-oxazol-3-yl]-1,3-thiazol-2-yl}piperidin-1-yl)ethanone(I-10)

To a solution of [3,5-bis-(difluoromethyl)-1H-pyrazol-1-yl]acetic acid(0.37 g) in dichloromethane (10 ml) are added, at 0° C., oxalyl chloride(0.57 g) and one drop of N,N-dimethylformamide. The reaction mixture isstirred at room temperature for 60 minutes. The solvent and the excessreagent are removed under reduced pressure. The solid residue isdissolved again in dichloromethane and added dropwise, at 0° C., to asolution of4-{4-[5-(2-nitrophenyl)-4,5-dihydro-1,2-oxazol-3-yl]-1,3-thiazol-2-yl}piperidiniumchloride (0.59 g) and triethylamine (2.1 ml) in dichloromethane (14 ml).The reaction mixture is stirred at room temperature for 20 h. Then it isadmixed with concentrated sodium hydrogencarbonate solution, and theaqueous phase is removed and extracted with ethyl acetate. The combinedorganic phases are dried over sodium sulphate and concentrated.Purification by column chromatography gives2-[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]-1-(4-{4-[5-(2-nitrophenyl)-4,5-dihydro-1,2-oxazol-3-yl]-1,3-thiazol-2-yl}piperidin-1-yl)ethanone(170 mg).

1-(4-{4-[5-(2-Aminophenyl)-4,5-dihydro-1,2-oxazol-3-yl]-1,3-thiazol-2-yl}piperidin-1-yl)-2-[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]ethanone(I-41)

To a solution of2-[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]-1-(4-{4-[5-(2-nitrophenyl)-4,5-dihydro-1,2-oxazol-3-yl]-1,3-thiazol-2-yl}piperidin-1-yl)ethanone(80 mg) in methanol (10 ml) is added, at room temperature, Pd/C (20 mg,10%). The reaction mixture is stirred under a hydrogen atmosphere atroom temperature for 3 hours, then volatile constituents are removedunder reduced pressure. Purification by column chromatography gives1-(4-{4-[5-(2-aminophenyl)-4,5-dihydro-1,2-oxazol-3-yl]-1,3-thiazol-2-yl}piperidin-1-yl)-2-[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]ethanone(25 mg).

2-[3,5-Bis(difluoromethyl)-1H-pyrazol-1-yl]-1-[4-(4-{5-[2-(cyclohexylmethoxy)phenyl]-4,5-dihydro-1,2-oxazol-3-yl}-1,3-thiazol-2-yl)piperidin-1-yl]ethanone(I-24)

Processes D and E

tert-Butyl4-(4-{5-[2-(cyclohexylmethoxy)phenyl]-4,5-dihydro-1,2-oxazol-3-yl}-1,3-thiazol-2-yl)piperidine-1-carboxylate(X-a-7)

To a solution of tert-butyl4-{4-[(hydroxyimino)methyl]-1,3-thiazol-2-yl}piperidine-1-carboxylate(2.90 g) and 1-(cyclohexylmethoxy)-2-vinylbenzene (2.40 g) in ethylacetate (300 ml) were added, at room temperature, potassiumhydrogencarbonate (4.60 g) and N-chlorosuccinimide (1.48 g), and thenone drop of water. The reaction mixture was stirred at 60° C., for 6 h,then admixed with ethyl acetate and water and extracted with ethylacetate. The organic extracts were dried over sodium sulphate andconcentrated under reduced pressure. The residue was purified bychromatography. This gave tert-butyl4-(4-{5-[2-(cyclohexylmethoxy)phenyl]-4,5-dihydro-1,2-oxazol-3-yl}-1,3-thiazol-2-yl)piperidine-1-carboxylate(3.40 g).

¹H NMR (DMSO-d₆, 400 MHz): δ_(ppm): 0.97-1.12 (m, 5H), 1.40 (s, 9H),1.50-1.80 (m, 8H), 1.98-2.06 (m, 2H), 2.81-2.96 (m, 2H), 3.74-3.81 (m,3H), 3.95-4.03 (m, 2H), 5.78 (dd, 1H), 6.92 (t, 1H), 7.00 (d, 1H),7.26-7.33 (m, 2H), 7.97 (s, 1H)

log P (pH2.7): 6.30

MS (ESI): 426 ([M+H-C₄H₉OCO]⁺)

Process G

4-(4-{5-[2-(Cyclohexylmethoxy)phenyl]-4,5-dihydro-1,2-oxazol-3-yl}-1,3-thiazol-2-yl)-piperidiniumchloride (XII-7)

To a solution of tert-butyl4-(4-{5-[2-(cyclohexylmethoxy)phenyl]-4,5-dihydro-1,2-oxazol-3-yl}-1,3-thiazol-2-yl)piperidine-1-carboxylate(3.20 g) in dichloromethane was added dropwise, at 0° C., a 4 molarsolution of hydrogen chloride (4.0 eq.) in 1,4-dioxane. The reactionmixture was stirred at 0° C. and then gradually warmed to roomtemperature. After stirring overnight, the solvent and excess hydrogenchloride were removed. This gave4-(4-{5-[2-(cyclohexylmethoxy)phenyl]-4,5-dihydro-1,2-oxazol-3-yl}-1,3-thiazol-2-yl)piperidiniumchloride (2.50 g).

¹H NMR (DMSO-d₆, 400 MHz): δ_(ppm): 0.92-1.14 (m, 5H), 1.51-1.81 (m,6H), 1.93-2.07 (m, 2H), 2.14-2.27 (m, 2H), 2.92-3.10 (m, 2H), 3.26-3.47(m, 4H), 3.71-3.86 (m, 3H), 5.80 (dd, 1H), 6.91 (t, 1H), 7.01 (d, 1H),7.25-7.34 (m, 2H), 8.01 (s, 1H), 9.30 (s, 1H), 9.52 (s, 1H)

log P (pH2.7): 1.90

MS (ESI): 426 ([M+H]⁺)

Process H

2-[3,5-Bis(difluoromethyl)-1H-pyrazol-1-yl]-1-[4-(4-{5-[2-(cyclohexylmethoxy)phenyl]-4,5-dihydro-1,2-oxazol-3-yl}-1,3-thiazol-2-yl)piperidin-1-yl]ethanone(I-24)

To a solution of [3,5-bis-(difluoromethyl)-1H-pyrazol-1-yl]acetic acid(1.49 g) in dichloromethane (10 ml) are added, at 0° C., oxalyl chloride(2.29 g) and one drop of N,N-dimethylformamide. The reaction mixture isstirred at room temperature for 60 minutes. The solvent and the excessreagent are removed under reduced pressure. The solid residue isdissolved again in dichloromethane and added dropwise, at 0° C., to asolution of4-(4-{5-[2-(cyclohexylmethoxy)phenyl]-4,5-dihydro-1,2-oxazol-3-yl}-1,3-thiazol-2-yl)piperidiniumchloride (2.55 g) and triethylamine (8.36 ml) in dichloromethane (14ml). The reaction mixture is stirred at room temperature for 20 h. Thenit is admixed with concentrated sodium hydrogencarbonate solution, andthe aqueous phase is removed and extracted with ethyl acetate. Thecombined organic phases are dried over sodium sulphate and concentrated.Purification by column chromatography gives2-[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]-1-[4-(4-{5-[2-(cyclohexylmethoxy)phenyl]-4,5-dihydro-1,2-oxazol-3-yl}-1,3-thiazol-2-yl)piperidin-1-yl]ethanone(1.87 g).

2-{3-[2-(1-{[3,5-Bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazol-4-yl]-1,2-oxazol-5-yl}benzaldehyde(I-31)

Processes D and E

tert-Butyl4-{4-[5-(2-formylphenyl)-1,2-oxazol-3-yl]-1,3-thiazol-2-yl}piperidine-1-carboxylate(X-b-1)

To a solution of tert-butyl4-(4-[(hydroxyimino)methyl]-1,3-thiazol-2-yl)piperidine-1-carboxylate(1.00 g) in DMF (10 ml) was added, at 50° C., N-chlorosuccinimide (0.51g), and the mixture was stirred for 30 minutes. At room temperature,triethylamine (1.34 ml) and 2-ethynylbenzaldehyde (0.54 g) were added tothe reaction mixture. After stirring at 50° C. for 2 hours, the reactionmixture was admixed with ethyl acetate and water and extracted withethyl acetate. The organic extracts were dried over sodium sulphate andconcentrated under reduced pressure. The residue was purified bychromatography. This gave tert-butyl4-{4-[5-(2-formylphenyl)-1,2-oxazol-3-yl]-1,3-thiazol-2-yl}piperidine-1-carboxylate(95 mg).

¹H NMR (DMSO-d₆): δ_(ppm): 1.42-1.41 (m, 9H), 1.69-1.50 (m, 2H),2.12-1.98 (m, 2H), 2.90 (bs, 2H), 3.40-3.28 (m, 1H), 4.10-3.95 (m, 2H),7.44 (s, 1H), 7.77 (dd, 1H), 7.87 (dd, 1H), 7.94 (d, 1H), 8.02 (d, 1H),8.29 (s, 1H), 10.29 (s, 1H)

log P (HCOOH): 4.10

MS (ESI): 340 ([M-COOC(CH)₃+2H]⁺)

Processes G and H

2-{3-[2-(1-{[3,5-Bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazol-4-yl]-1,2-oxazol-5-yl}benzaldehyde(I-31)

To a solution of tert-butyl4-{4-[5-(2-formylphenyl)-1,2-oxazol-3-yl]-1,3-thiazol-2-yl}piperidine-1-carboxylate(95 mg) in dichloromethane was added dropwise, at 0° C., a 4 molarsolution of hydrogen chloride (2 ml) in 1,4-dioxane. The reactionmixture was stirred at 0° C., and then gradually warmed to roomtemperature. After stirring overnight, the solvent and excess hydrogenchloride were removed. This gave4-({4-[5-(2-formylphenyl)-1,2-oxazol-3-yl]-1,3-thiazol-2-yl}piperidiniumchloride (XII-8).

To a solution of [3,5-bis-(difluoromethyl)-1H-pyrazol-1-yl]acetic acid(51 mg) in dichloromethane (2 ml) are added, at 0° C., oxalyl chloride(57 μL) and one drop of N,N-dimethylformamide. The reaction mixture isstirred at room temperature for 60 minutes. The solvent and the excessreagent are removed under reduced pressure. The solid residue is againdissolved in dichloromethane and added dropwise at 0° C. to a solutionof4-(4-[5-(2-formylphenyl)-1,2-oxazol-3-yl]-1,3-thiazol-2-yl)piperidiniumchloride and triethylamine (90 μl) in dichloromethane (2 ml). Thereaction mixture is stirred at room temperature for 3 h. Then it isadmixed with concentrated sodium hydrogencarbonate solution, and theaqueous phase is removed and extracted with ethyl acetate. The combinedorganic phases are dried over sodium sulphate and concentrated.Purification by column chromatography gives2-{3-[2-(1-{[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazol-4-yl]-1,2-oxazol-5-yl}benzaldehyde(36 mg).

Cyclopropylmethyl2-{3-[2-(1-{[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazol-4-yl]-4,5-dihydro-1,2-oxazol-5-yl}benzoate(I-13)

Processes D and E

tert-Butyl4-(4-{5-[2-(methoxycarbonyl)phenyl]-4,5-dihydro-1,2-oxazol-3-yl}-1,3-thiazol-2-yl)piperidine-1-carboxylate(X-a-8)

tert-Butyl4-{4-[(Z/E)-(hydroxyimino)methyl]-1,3-thiazol-2-yl}piperidine-1-carboxylate(600 mg) and methyl 2-vinylbenzoate (406 mg) were reacted analogously toI-31 (Processes D and E). This gave tert-butyl4-(4-{5-[2-(methoxycarbonyl)phenyl]-4,5-dihydro-1,2-oxazol-3-yl}-1,3-thiazol-2-yl)piperidine-1-carboxylate(643 mg).

¹H NMR (DMSO-d₆): δ_(ppm): 1.40 (s, 9H), 1.60-1.49 (m, 2H), 2.05-1.96(m, 2H), 2.98-2.75 (m, 2H), 3.20 (dd, 1H), 3.26-3.20 (m, 1H), 3.88 (s,3H), 4.02 (dd, 1H), 4.05-3.93 (m, 2H), 6.30 (dd, 1H), 7.48 (dd, 1H),7.55 (d, 1H), 7.65 (dd, 1H), 7.96 (d, 1H), 8.00 (s, 1H)

log P (HCOOH): 4.14

MS (ESI): 372 ([M-COOC(CH₃)₃+2H]⁺)

2-(3-{2-[1-(tert-Butoxycarbonyl)piperidin-4-yl]-1,3-thiazol-4-yl}-4,5-dihydro-1,2-oxazol-5-yl)benzoicacid (X-a-9)

To a solution of tert-butyl4-(4-{5-[2-(methoxycarbonyl)phenyl]-4,5-dihydro-1,2-oxazol-3-yl}-1,3-thiazol-2-yl)piperidine-1-carboxylate(643 mg) in tetrahydrofuran (4 ml) and water (0.8 ml) is added, at roomtemperature, lithium hydroxide monohydrate (86 mg). The mixture isstirred at room temperature for 2 h and then admixed with ice-cold 1NHCl solution. The aqueous phase is extracted with ethyl acetate and thenthe combined organic phases are dried with sodium sulphate. The solidsare filtered off and the solvent is distilled off. This gives2-(3-{2-[1-(tert-butoxycarbonyl)piperidin-4-yl]-1,3-thiazol-4-yl}-4,5-dihydro-1,2-oxazol-5-yl)benzoicacid (377 mg).

¹H NMR (DMSO-d₆): δ_(ppm): 1.40 (s, 9H), 1.56-1.48 (m, 2H), 2.04-1.99(m, 2H), 2.88 (bs, 2H), 3.18 (dd, 1H), 3.28-3.19 (m, 1H), 4.04-3.98 (m,3H), 6.48 (dd, 1H), 7.43 (d, 1H), 7.52 (d, 1H), 7.60 (dd, 1H), 7.96 (d,1H), 8.01 (s, 1H)

log P (HCOOH): 3.18

MS (ESI): 358 ([M-COOC(CH₃)₃+2H]⁺)

tert-Butyl4-[4-(5-{2-[(cyclopropylmethoxy)carbonyl]phenyl}-4,5-dihydro-1,2-oxazol-3-yl)-1,3-thiazol-2-yl]piperidine-1-carboxylate(X-a-10)

To a solution of 2-(3-{2-[1-(tert-butoxycarbonyl)piperidin-4-yl]-1,3-thiazol-4-yl}-4,5-dihydro-1,2-oxazol-5-yl)benzoicacid (300 mg) in dichloromethane (10 ml) are added, at room temperature,cyclopropylmethanol (47 mg), 4-dimethylaminopyridine (8 mg) and1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide (132 mg). The mixture isstirred at room temperature for 3 hours and then admixed with water. Theaqueous phase is removed and extracted with ethyl acetate. The combinedorganic phases are dried over sodium sulphate and concentrated underreduced pressure. The residue is purified by chromatography. This givestert-butyl4-[4-(5-{2-[(cyclopropylmethoxy)carbonyl]phenyl}-4,5-dihydro-1,2-oxazol-3-yl)-1,3-thiazol-2-yl]piperidine-1-carboxylate(270 mg).

¹H NMR (DMSO-d₆): δ_(ppm): 0.40-0.37 (m, 2H), 0.61-0.56 (m, 2H),1.30-1.22 (m, 1H), 1.40 (s, 9H), 1.59-1.48 (m, 2H), 2.05-1.98 (m, 2H),2.88 (bs, 2H), 3.26-3.18 (m, 2H), 4.08-3.96 (m, 3H), 4.15 (dd, 2H), 6.31(dd, 1H), 7.48 (dd, 1H), 7.56 (d, 1H), 7.65 (dd, 1H), 7.96 (d, 1H), 8.00(s, 1H)

log P (HCOOH): 4.99

MS (ESI): 412 ([M-COOC(CH₃)₃+2H]⁺)

Processes G and H

Cyclopropylmethyl2-{3-[2-(1-{[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazol-4-yl]-4,5-dihydro-1,2-oxazol-5-yl}benzoate(I-13)

tert-Butyl4-[4-(5-{2-[(cyclopropylmethoxy)carbonyl]phenyl}-4,5-dihydro-1,2-oxazol-3-yl)-1,3-thiazol-2-yl]piperidine-1-carboxylate(270 mg) was reacted analogously to I-31 (Processes G and H). This gavecyclopropylmethyl2-{3-[2-(1-{[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazol-4-yl]-4,5-dihydro-1,2-oxazol-5-yl}benzoate(136 mg).

Methyl2-{3-[2-(1-{[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazol-4-yl]-4,5-dihydro-1,2-oxazol-5-yl}benzoate(I-43) and methyl2-{3-[2-(1-{[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-5-chloro-1,3-thiazol-4-yl]-4,5-dihydro-1,2-oxazol-5-yl}benzoate(I-46) 4-(4-Formyl-1,3-thiazol-2-yl)piperidinium chloride

To tert-butyl 4-(4-formyl-1,3-thiazol-2-yl)piperidine-1-carboxylate (10g) was added dropwise, at 0° C., a 4 molar solution of hydrogen chloridein 1,4-dioxane (100 ml). The reaction mixture was stirred at 0° C., andthen gradually warmed to room temperature. After stirring overnight, thesolvent and excess hydrogen chloride were removed. This gave4-(4-formyl-1,3-thiazol-2-yl)piperidinium chloride (9 g).

¹H NMR (DMSO-d₆): δ_(ppm): 2.05-1.94 (m, 2H), 2.25-2.17 (m, 2H),3.09-2.97 (m, 2H), 3.37-3.30 (m, 2H), 3.48-3.40 (m, 1H), 8.68 (s, 1H),9.15 (bs, 1H), 9.32 (bs, 1H), 9.90 (s, 1H)

2-(1-{([3,5-Bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl)}piperidin-4-yl)-1,3-thiazole-4-carbaldehyde(VI-2)

To a solution of [3,5-bis-(difluoromethyl)-1H-pyrazol-1-yl]acetic acid(3.64 g) in dichloromethane (20 ml) are added, at 0° C., oxalyl chloride(3.5 ml) and one drop of N,N-dimethylformamide. The reaction mixture isstirred at room temperature for 10 minutes. The solvent and the excessreagent are removed under reduced pressure. The solid residue is againdissolved in dichloromethane and, at 0° C., added dropwise to a solutionof 4-(4-formyl-1,3-thiazol-2-yl)piperidinium chloride (3.11 g) andtriethylamine (5.6 ml) in dichloromethane (20 ml). The reaction mixtureis stirred at room temperature for 3 hours. Then it is admixed withconcentrated sodium hydrogencarbonate solution, and the aqueous phase isremoved and extracted with ethyl acetate. The combined organic phasesare dried over sodium sulphate and concentrated. Purification by columnchromatography gives2-(1-{[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carbaldehyde(4.52 g).

¹H NMR (DMSO-d₆): δ_(ppm): 1.65-1.53 (m, 1H), 1.89-1.77 (m, 1H),2.18-2.08 (m, 2H), 2.90-2.80 (m, 1H), 3.48-3.22 (m, 2H), 4.00-3.93 (m,1H), 4.38-4.31 (m, 1H), 5.34 (d, 1H), 5.39 (d, 1H), 6.90 (s, 1H), 7.02(t, 1H), 7.18 (t, 1H), 8.65 (s, 1H), 9.90 (s, 1H)

log P (HCOOH): 1.93

MS (ESI): 405 ([M+H]⁺)

Processes D and E

2-(1-{[3,5-Bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carbaldehydeoxime

To a solution of2-(1-{[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carbaldehyde(487 mg) in ethanol (5 ml) was added dropwise hydroxylamine (50% inwater, 44 μl) at room temperature. The reaction mixture was stirred at60° C., for 2 hours, then the solvent was removed under reducedpressure. This gave2-(1-{[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carbaldehydeoxime (454 mg).

log P (HCOOH): 1.93 and 1.98 (2 isomers)

MS (ESI): 420 ([M+H]⁺)

Methyl2-{3-[2-(1-{[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazol-4-yl]-4,5-dihydro-1,2-oxazol-5-yl}benzoate(I-43) and methyl2-{3-[2-(1-{[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-5-chloro-1,3-thiazol-4-yl]-4,5-dihydro-1,2-oxazol-5-yl}benzoate(I-46)

To a solution of2-(1-{[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carbaldehydeoxime (1.00 g) in DMF (4 ml) was added, at 50° C., N-chlorosuccinimide(382 mg) and the mixture was stirred for 30 minutes. At roomtemperature, triethylamine (1 ml) and methyl 2-vinylbenzoate (0.50 g)were added to the reaction mixture. After stirring at 50° C., for 2hours, the reaction mixture was admixed with ethyl acetate and water andextracted with ethyl acetate. The organic extracts were dried oversodium sulphate and concentrated under reduced pressure. The residue waspurified by chromatography. This gave methyl2-{3-[2-(1-{[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazol-4-yl]-4,5-dihydro-1,2-oxazol-5-yl}benzoate(287 mg) and methyl2-{3-[2-(1-{[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-5-chloro-1,3-thiazol-4-yl]-4,5-dihydro-1,2-oxazol-5-yl}benzoate(193 mg).

2-{3-[2-(1-{[3,5-Bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazol-4-yl]-4,5-dihydro-1,2-oxazol-5-yl}-N-cyclopropylbenzamide(I-27)2-{3-[2-(1-{[3,5-Bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazol-4-yl]-4,5-dihydro-1,2-oxazol-5-yl}benzoicacid

To a solution of methyl2-{3-[2-(1-({[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazol-4-yl]-4,5-dihydro-1,2-oxazol-5-yl}benzoate(208 mg) in tetrahydrofuran (1 ml) and water (0.2 ml) is added, at roomtemperature, lithium hydroxide monohydrate (23 mg). The mixture isstirred at room temperature for 2 h and then admixed with ice-cold 1NHCl solution. The aqueous phase is extracted with ethyl acetate and thenthe combined organic phases are dried with sodium sulphate. The solidsare filtered off and the solvent is distilled off. This gives2-{3-[2-(1-{[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]-acetyl}piperidin-4-yl)-1,3-thiazol-4-yl]-4,5-dihydro-1,2-oxazol-5-yl}benzoicacid (158 mg).

¹H NMR (DMSO-d₆): δ_(ppm): 1.61-1.50 (m, 1H), 1.59-1.73 (m, 1H),2.15-2.02 (m, 2H), 2.87-2.78 (m, 1H), 3.48-3.15 (m, 3H), 4.05-3.92 (m,2H), 4.38-4.30 (m, 1H), 5.34 (d, 1H), 5.42 (d, 1H), 6.38 (dd, 1H), 6.89(s, 1H), 7.02 (t, 1H), 7.17 (t, 1H), 7.43 (dd, 1H), 7.54 (d, 1H), 7.60(dd, 1H), 7.96 (d, 1H), 8.02 (s, 1H)

log P (HCOOH): 2.63

MS (ESI): 566 ([M+H]⁺)

2-{3-[2-(1-{[3,5-Bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazol-4-yl]-4,5-dihydro-1,2-oxazol-5-yl}-N-cyclopropylbenzamide(I-27)

To a solution of2-{3-[2-(1-{[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazol-4-yl]-4,5-dihydro-1,2-oxazol-5-yl}benzoicacid (105 mg) in dichloromethane (10 ml) are added, at room temperature,cyclopropanamine (11 mg), 4-dimethylaminopyridine (2 mg) and1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide (37 mg). The mixture isstirred at room temperature for 3 hours and then admixed with water. Theaqueous phase is removed and extracted with ethyl acetate. The combinedorganic phases are dried over sodium sulphate and concentrated underreduced pressure. The residue is purified by chromatography. This gives2-{3-[2-(1-{[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazol-4-yl]-4,5-dihydro-1,2-oxazol-5-yl}-N-cyclopropylbenzamide(78 mg).

2-[3,5-Bis(difluoromethyl)-1H-pyrazol-1-yl]-1-[4-(4-{5-[2-(hydroxymethyl)phenyl]-4,5-dihydro-1,2-oxazol-3-yl}-1,3-thiazol-2-yl)piperidin-1-yl]ethanone(I-45)

To a solution of2-{3-[2-(1-{[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazol-4-yl]-4,5-dihydro-1,2-oxazol-5-yl}benzaldehyde(1.9 g) in methanol (50 ml) was added, at 0° C., sodium borohydride(0.16 g), and then the mixture was stirred at room temperature for 2hours. Subsequently, the reaction mixture was admixed at 0° C., with 0.1molar hydrochloric acid and ethyl acetate. The organic extracts weredried over sodium sulphate and concentrated under reduced pressure. Theresidue was purified by chromatography. This gave2-[3,5-bis(difluoromethyl)-1H-pyrazol--yl]-1-[4-(4-{5-[2-(hydroxymethyl)phenyl]-4,5-dihydro-1,2-oxazol-3-yl}-1,3-thiazol-2-yl)piperidin-1-yl]-ethanone(1.1 g).

2-[3,5-Bis(difluoromethyl)-1H-pyrazol-1-yl]-1-[4-(4-{5-[2-(chloromethyl)phenyl]-4,5-dihydro-1,2-oxazol-3-yl}-1,3-thiazol-2-yl)piperidin-1-yl]ethanone(I-44)

To a solution of2-[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]-1-[4-(4-{5-[2-(hydroxymethyl)phenyl]-4,5-dihydro-1,2-oxazol-3-yl}-1,3-thiazol-2-yl)piperidin-1-yl]ethanone(0.55 g) in dichloromethane (10 ml) were added, at room temperature,thionyl chloride (0.24 g) and one drop of DMF, and the mixture was thenrefluxed for 2 hours. Subsequently, the reaction mixture wasconcentrated under reduced pressure. This gave, without furtherpurification,2-[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]-1-[4-(4-{5-[2-(chloromethyl)phenyl]-4,5-dihydro-1,2-oxazol-3-yl}-1,3-thiazol-2-yl)piperidin-1-yl]ethanone(0.59 g).

2-[3,5-Bis(difluoromethyl)-1H-pyrazol-1-yl]-1-{4-[4-(5-{2-[(2-methoxyethoxy)methyl]phenyl}-4,5-dihydro-1,2-oxazol-3-yl)-1,3-thiazol-2-yl]piperidin-1-yl}ethanone(I-11)

2-Methoxyethanol (1.5 ml) was admixed at room temperature with sodiumhydride (60%, 17 mg) and then stirred at room temperature for 2 hours.To this mixture was added dropwise a solution of2-[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]-1-[4-(4-{5-[2-(chloromethyl)phenyl]-4,5-dihydro-1,2-oxazol-3-yl}-1,3-thiazol-2-yl)piperidin-1-yl]ethanone(0.20 g) in 2-methoxyethanol (1.5 g), and the mixture was then stirredat room temperature for 16 hours. Subsequently, the reaction mixture wasadmixed with water and dichloromethane. The organic extracts were driedover sodium sulphate and concentrated under reduced pressure. Theresidue was purified by chromatography. This gave2-[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]-1-{4-[4-(5-{2-[(2-methoxyethoxy)methyl]phenyl}-4,5-dihydro-1,2-oxazol-3-yl)-1,3-thiazol-2-yl]piperidin-1-yl}ethanone(0.11 g).

2-[3,5-Bis(difluoromethyl)-1H-pyrazol-1-yl]-1-{4-[4-(5-{2-[(ethylsulphanyl)methyl]phenyl}-4,5-dihydro-1,2-oxazol-3-yl)-1,3-thiazol-2-yl]piperidin-1-yl}ethanone(I-12)2-{3-[2-(1-{[3,5-Bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazol-4-yl]-4,5-dihydro-1,2-oxazol-5-yl}benzylimidothiocarbamate

A mixture of2-[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]-1-[4-(4-{5-[2-(chloromethyl)phenyl]-4,5-dihydro-1,2-oxazol-3-yl}-1,3-thiazol-2-yl)piperidin-1-yl]ethanone(0.20 g) and thiourea (29 mg) in ethanol (5 ml) was refluxed for 1 hour.Subsequently, the reaction mixture was concentrated under reducedpressure and the residue was admixed with 5% sodium hydrogencarbonatesolution and ethyl acetate. The organic extracts were dried over sodiumsulphate and concentrated under reduced pressure. The residue wasfiltered through silica gel in a mixture of cyclohexane and ethylacetate (1:2). This gave2-{3-[2-(1-{[3,5-bis(difluoro-methyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazol-4-yl]-4,5-dihydro-1,2-oxazol-5-yl}benzylimidothiocarbamate (0.15 g).

¹H NMR: δ_(ppm): 1.58 (m, 1H), 1.80 (m, 1H), 2.18-2.05 (m, 2H), 2.82 (m,1H), 3.42-3.20 (m, 3H), 3.97 (m, 2H), 4.32 (m, 2H), 5.40 (dd, 2H), 6.06(dd, 1H), 6.59 (bs, 1H), 6.91 (s, 1H), 7.03 (t, 1H), 7.18 (t, 1H),7.45-7.25 (m, 4H), 8.03 (s, 1H)

log P (HCOOH): 1.68

2-[3,5-Bis(difluoromethyl)-1H-pyrazol-1-yl]-1-{4-[4-(5-{2-[(ethylsulphanyl)methyl]phenyl}-4,5-dihydro-1,2-oxazol-3-yl)-1,3-thiazol-2-yl]piperidin-1-yl}ethanone(I-12)

To a solution of2-{3-[2-(1-{[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazol-4-yl]-4,5-dihydro-1,2-oxazol-5-yl}benzylimidothiocarbamate (0.15 g) in toluene (5 ml) were added 50% sodiumhydroxide solution (0.5 ml), iodoethane (42 mg) and one drop oftetra-n-butylammonium bromide. Thereafter, the mixture was stirredvigorously at room temperature for 2 hours. Subsequently, the reactionmixture was admixed with water and ethyl acetate. The organic extractswere dried over sodium sulphate and concentrated under reduced pressure.The residue was purified by chromatography. This gave2-[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]-1-{4-[4-(5-{2-[(ethylsulphanyl)methyl]phenyl}-4,5-dihydro-1,2-oxazol-3-yl)-1,3-thiazol-2-yl]piperidin-1-yl}ethanone(50 mg).

1-[4-(4-{5-[2-(Allyloxy)phenyl]-4,5-dihydro-1,2-oxazol-3-yl}-1,3-thiazol-2-yl)piperidin-1-yl]-2-[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]ethanone(I-14)

To a solution of2-[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]-1-(4-{4-[5-(2-hydroxyphenyl)-4,5-dihydro-1,2-oxazol-3-yl]-1,3-thiazol-2-yl}piperidin-1-yl)ethanone(81 mg) and potassium carbonate (105 mg) in acetone (5 ml) is added, atroom temperature, allyl bromide (73 mg). The reaction mixture is stirredat reflux for 5 h. Then the mixture is admixed with water and extractedwith ethyl acetate. The combined organic phases are dried over sodiumsulphate and concentrated. Purification by column chromatography gives1-[4-(4-{5-[2-(allyloxy)phenyl]-4,5-dihydro-1,2-oxazol-3-yl}-1,3-thiazol-2-yl)piperidin-1-yl]-2-[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]ethanone(48 mg).

2-[3,5-Bis(difluoromethyl)-1H-pyrazol-1-yl]-1-{4-[4-(5-{2-[(3-methylbut-2-en-1-yl)oxy]phenyl}-4,5-dihydro-1,2-oxazol-3-yl)-1,3-thiazol-2-yl]piperidin-1-yl}ethanone(I-20) and2-[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]-1-{4-[4-(5-{2-[(2-methylprop-2-en-1-yl)oxy]phenyl}-4,5-dihydro-1,2-oxazol-3-yl)-1,3-thiazol-2-yl]piperidin-1-yl}ethanone(I-18) were reacted analogously to I-142-[3,5-Bis(difluoromethyl)-1H-pyrazol-1-yl]-1-[4-(4-{5-[2-(2-methoxyethoxy)phenyl]-4,5-dihydro-1,2-oxazol-3-yl}-1,3-thiazol-2-yl)piperidin-1-yl]ethanone(I-19)

To a solution of2-[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]-1-(4-{4-[5-(2-hydroxyphenyl)-4,5-dihydro-1,2-oxazol-3-yl]-1,3-thiazol-2-yl}piperidin-1-yl)ethanone(81 mg) and potassium carbonate (105 mg) in N,N-dimethylformamide (5 ml)are added, at room temperature, 1-bromo-2-methoxyethane (84 mg) andpotassium iodide (2.5 mg). The reaction mixture is stirred at 80° C.,for 3 h. Then the mixture is admixed with water and extracted with ethylacetate. The combined organic phases are dried over sodium sulphate andconcentrated. Purification by column chromatography gives2-[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]-1-[4-(4-{5-[2-(2-methoxyethoxy)phenyl]-4,5-dihydro-1,2-oxazol-3-yl}-1,3-thiazol-2-yl)piperidin-1-yl]ethanone(41 mg).

2-[3,5-Bis(difluoromethyl)-1H-pyrazol-1-yl]-1-[4-(4-{5-[3-(2-methoxyethoxy)phenyl]-4,5-dihydro-1,2-oxazol-3-yl}-1,3-thiazol-2-yl)piperidin-1-yl]ethanone(I-28)

Processes D and E

tert-Butyl4-(4-{5-[3-(2-methoxyethoxy)phenyl]-4,5-dihydro-1,2-oxazol-3-yl}-1,3-thiazol-2-yl)piperidine-1-carboxylate(X-a-11)

tert-Butyl4-{-[(hydroxyimino)methyl]-1,3-thiazol-2-yl}piperidine-1-carboxylate(250 mg) and 1-(2-methoxyethoxy)-3-vinylbenzene were reacted analogouslyto I-31 (Processes D and E). This gave tert-butyl4-(4-{5-[3-(2-methoxyethoxy)phenyl]-4,5-dihydro-1,2-oxazol-3-yl}-1,3-thiazol-2-yl)piperidine-1-carboxylate(170 mg)

¹H NMR (DMSO-d₆): δ_(ppm): 8.00 (s, 1H), 7.29 (t, 1H), 7.10-6.80 (m,3H), 5.68 (dd, 1H), 4.15-3.95 (m, 4H), 3.84 (dd, 1H), 3.70-3.60 (m, 2H),3.45-3.20 (m), 2.95-2.80 (m, 2H), 2.08-1.98 (m, 2H), 1.63-1.48 'm, 2H),1.40 (s, 9H)

The 1-(2-methoxyethoxy)-3-vinylbenzene reactant was synthesizedproceeding from 3-(2-methoxy-ethoxy)benzaldehyde by methods familiar tothose skilled in the art (Wittig reaction: Chem. Rev. 1989, 89,863-927).

Processes G and H

2-[3,5-Bis(difluoromethyl)-1H-pyrazol-1-yl]-1-[4-(4-{5-[3-(2-methoxyethoxy)phenyl]-4,5-dihydro-1,2-oxazol-3-yl}-1,3-thiazol-2-yl)piperidin-1-yl]ethanone(I-28)

tert-Butyl4-(4-{5-[3-(2-methoxyethoxy)phenyl]-4,5-dihydro-1,2-oxazol-3-yl}-1,3-thiazol-2-yl)piperidine-1-carboxylate(279 mg) was reacted analogously to I-31 (Processes G and H). This gave2-[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]-1-[4-(4-{5-[3-(2-methoxyethoxy)-phenyl]-4,5-dihydro-1,2-oxazol-3-yl}-1,3-thiazol-2-yl)piperidin-1-yl]ethanone(180 mg).

2-[3,5-Bis(difluoromethyl)-1H-pyrazol-1-yl]-1-(4-{4-[5-(2-chloro-6-hydroxyphenyl)-4,5-dihydro-1,2-oxazol-3-yl]-1,3-thiazol-2-yl}piperidin-1-yl)ethanone(I-54)

Processes D and E

tert-Butyl4-{4-[5-(2-chloro-6-hydroxyphenyl)-4,5-dihydro-1,2-oxazol-3-yl]-1,3-thiazol-2-yl}piperidine-1-carboxylate(X-a-12)

To a solution of tert-butyl4-{4-[(hydroxyimino)methyl]-1,3-thiazol-2-yl}piperidine-1-carboxylate(400 mg) in ethyl acetate (10 ml) was added N-chlorosuccinimide (206mg). The reaction mixture is stirred at reflux for 30 min. To thereaction mixture were added 3-chloro-2-vinylphenol (397 mg) andpotassium hydrogencarbonate (257 mg) at room temperature, and then onedrop of water. After stirring at room temperature overnight, thereaction mixture was admixed with ethyl acetate and water and extractedwith ethyl acetate. The organic extracts were dried over sodium sulphateand concentrated under reduced pressure. The residue was purified bychromatography. This gave tert-butyl4-{4-[5-(2-chloro-6-hydroxyphenyl)-4,5-dihydro-1,2-oxazol-3-yl]-1,3-thiazol-2-yl}piperidine-1-carboxylate(345 mg).

¹H NMR (DMSO-d₆): δ_(ppm): 7.95 (s, 1H), 7.18 (t, 1H), 6.92 (d, 1H),6.82 (d, 1H), 6.17 (dd, 1H), 4.1-3.95 (m), 3.30-3.15 (m), 3.05-2.75 (m,2H), 2.08-2.0 (m, 2H), 1.62-1.50 (m, 2H), 1.40 (s, 9H)

In this case too, the 3-chloro-2-vinylphenol reactant was synthesizedproceeding from 2-chloro-6-hydroxybenzaldehyde by synthesis methodsfamiliar to those skilled in the art (Wittig reaction: Chem. Rev. 1989,89, 863-927).

Processes G and H

2-[3,5-Bis(difluoromethyl)-1H-pyrazol-1-yl]-1-(4-{4-[5-(2-chloro-6-hydroxyphenyl)-4,5-dihydro-1,2-oxazol-3-yl]-1,3-thiazol-2-yl}piperidin-1-yl)ethanone(I-54)

To a solution of tert-butyl4-{4-[5-(2-chloro-6-hydroxyphenyl)-4,5-dihydro-1,2-oxazol-3-yl]-1,3-thiazol-2-yl}piperidine-1-carboxylate(346 mg) in dichloromethane was added dropwise, at 0° C., a 4 molarsolution of hydrogen chloride (4.0 eq.) in 1,4-dioxane. The reactionmixture was stirred at 0° C., and then gradually warmed to roomtemperature. After stirring for 5 hours, the solvent and excess hydrogenchloride were removed. This gave4-{4-[5-(2-chloro-6-hydroxyphenyl)-4,5-dihydro-1,2-oxazol-3-yl]-1,3-thiazol-2-yl}piperidinium chloride (XII-9).

To a solution of [3,5-bis-(difluoromethyl)-1H-pyrazol-1-yl]acetic acid(177 mg) in dichloromethane (40 ml) are added, at 0° C., oxalyl chloride(290 mg) and one drop of N,N-dimethylformamide. The reaction mixture isstirred at room temperature for 2 hours. The solvent and the excessreagent are removed under reduced pressure. The solid residue is againdissolved in dichloromethane and, at 0° C., added dropwise to a solutionof4-{4-[5-(2-chloro-6-hydroxyphenyl)-4,5-dihydro-1,2-oxazol-3-yl]-1,3-thiazol-2-yl}piperidiniumchloride and triethylamine (5.0 eq.) in dichloromethane (25 ml). Thereaction mixture is stirred at room temperature overnight. Then it isadmixed with concentrated sodium hydrogencarbonate solution, and theaqueous phase is removed and extracted with ethyl acetate. The combinedorganic phases are dried over sodium sulphate and concentrated.Purification by column chromatography gives2-[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]-1-(4-{4-[5-(2-chloro-6-hydroxyphenyl)-4,5-dihydro-1,2-oxazol-3-yl]-1,3-thiazol-2-yl}piperidin-1-yl)ethanone(110 mg).

¹H NMR (DMSO-d₆): δ_(ppm): 10.28 (s, 1H), 7.98 (s, 1H), 7.30-6.80 (m,6H), 6.17 (dd, 1H), 5.40 (dd, 2H), 4.36 (d, 1H), 3.97 (d, 1H), 3.71-3.55(m, 2H), 3.32-3.24 (m, 1H), 2.84 (t, 1H), 2.16-2.08 (m, 2H), 1.85-1.75(m, 1H), 1.62-1.53 (m, 1H).

Log P (HCOOH): 2.94

1-[4-(4-{5-[2-(Allyloxy)-6-chlorophenyl]-4,5-dihydro-1,2-oxazol-3-yl}-1,3-thiazol-2-yl)piperidin-1-yl]-2-[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]ethanone(I-51)

To a solution of2-[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]-1-(4-{4-[5-(2-chloro-6-hydroxyphenyl)-4,5-dihydro-1,2-oxazol-3-yl]-1,3-thiazol-2-yl}piperidin-1-yl)ethanone(39 mg) and potassium carbonate (47 mg) in acetone (5 ml) is added, atroom temperature, allyl bromide (33 mg). The reaction mixture is stirredat reflux for 5 h. Then the mixture is admixed with water and extractedwith ethyl acetate. The combined organic phases are dried over sodiumsulphate and concentrated. Purification by column chromatography gives1-[4-(4-{5-[2-allyloxy)-6-chlorophenyl]-4,5-dihydro-1,2-oxazol-3-yl}-1,3-thiazol-2-yl)piperidin-1-yl]-2-[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]ethanone(26 mg).

2-[3,5-Bis(difluoromethyl)-1H-pyrazol-1-yl]-1-[4-(4-{5-[2-chloro-6-(prop-2-yn-1-yloxy)phenyl]-4,5-dihydro-1,2-oxazol-3-yl}-1,3-thiazol-2-yl)piperidin-1-yl]ethanone(I-49)

To a solution of2-[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]-1-(4-{4-[5-(2-chloro-6-hydroxyphenyl)-4,5-dihydro-1,2-oxazol-3-yl]-1,3-thiazol-2-yl}piperidin-1-yl)ethanone(33 mg) and potassium carbonate (12 mg) in N,N-dimethylformamide (5 ml)are added, at room temperature, potassium iodide (5 mg) and3-bromoprop-1-yne (11 mg). The reaction mixture is stirred at 80° C.,for 9 h. Then the mixture is admixed with dilute hydrochloric acid andextracted with ethyl acetate. The combined organic phases are dried oversodium sulphate and concentrated. Purification by column chromatographygives2-[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]-1-[4-(4-{5-[2-chloro-6-(prop-2-yn-1yloxy)phenyl]-4,5-dihydro-1,2-oxazol-3-yl}-1,3-thiazol-2-yl)piperidin-1-yl]ethanone(19 mg).

2-[3,5-Bis(difluoromethyl)-1H-pyrazol-1-yl]-1-[4-(4-{5-[2-chloro-6-(2-methoxyethoxy)phenyl]-4,5-dihydro-1,2-oxazol-3-yl}-1,3-thiazol-2-yl)piperidin-1-yl]ethanone(I-50)

To a solution of2-[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]-(4-{4-[5-(2-chloro-6-hydroxyphenyl)-4,5-dihydro-1,2-oxazol-3-yl]-1,3-thiazol-2-yl}piperidin-1-yl)ethanone(39 mg) and potassium carbonate (47 mg) in N,N-dimethylformamide (5 ml)are added, at room temperature, 1-bromo-2-methoxyethane (38 mg) andpotassium iodide (1.1 mg). The reaction mixture is stirred at 80° C.,for 3 h. Then the mixture is admixed with water and extracted with ethylacetate. The combined organic phases are dried over sodium sulphate andconcentrated. Purification by column chromatography gives2-[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]-1-[4-(4-{5-[2-chloro-)-(2-methoxyethoxy)-phenyl]-4,5-dihydro-1,2-oxazol-3-yl}-1,3-thiazol-2-yl)piperidin-1-yl]ethanone(17 mg).

2-{3-[2-(1-{[3,5-Bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazol-4-yl]-4,5-dihydro-1,2-oxazol-5-yl}-3-fluorobenzaldehyde(I-17) 3-Fluoro-2-vinylbenzaldehyde

To a solution of 1-bromo-3-fluoro-2-vinylbenzene (900 mg) in THF (40 ml)was added dropwise, at −78° C., n-butyllithium (3.4 ml 1.6 M/hexane).After 60 minutes. N,N-dimethylformamide (0.69 ml) was added dropwise at−78° C. After stirring at −78° C., for 60 minutes, the reaction mixturewas admixed with water and then warmed to room temperature. Then themixture was admixed with water and extracted with ethyl acetate. Thecombined organic phases were dried over sodium sulphate andconcentrated. Purification by column chromatography gives3-fluoro-2-vinylbenzaldehyde (160 mg).

In this case too, the 1-bromo-3-fluoro-2-vinylbenzene reactant wassynthesized proceeding from 2-bromo-6-fluorobenzaldehyde by synthesismethods familiar to those skilled in the art (Wittig reaction: Chem.Rev. 1989, 89, 863-927).

Processes D and E

tert-Butyl4-{4-[5-(2-fluoro-6-formylphenyl)-4,5-dihydro-1,2-oxazol-3-yl]-1,3-thiazol-2-yl}piperidine-1-carboxylate(X-a-13)

To a solution of tert-butyl4-{4-[(hydroxyimino)methyl]-1,3-thiazol-2-yl}piperidine-1-carboxylate(166 mg) in ethyl acetate (10 ml) was added N-chlorosuccinimide (85.5mg). The reaction mixture was stirred at reflux for 30 min. To thisreaction mixture were added, at room temperature,3-fluoro-2-vinylbenzaldehyde (160 mg) and potassium hydrogencarbonate(106.7 mg), and then one drop of water. After stirring at roomtemperature overnight, the reaction mixture was admixed with ethylacetate and water and extracted with ethyl acetate. The organic extractswere dried over sodium sulphate and concentrated under reduced pressure.The residue was purified by chromatography. This gave tert-butyl4-{4-[5-(2-fluoro-6-formylphenyl)-4,5-dihydro-1,2-oxazol-3-yl]-1,3-thiazol-2-yl}piperidine-1-carboxylate(110 mg)

¹H NMR (DMSO-d₆): 10.26 (s, 1H), 8.03 (s, 1H), 7.76 (dd, 1H), 7.68-7.64(m, 1H), 7.62-7.57 (m, 1H), 6.55 (t, 1H), 4.08-3.90 (m, 3H), 3.53 (dd,1H), 3.40-3.30 (m, 1H), 2.05-2.00 (m, 2H), 1.62-1.52 (m, 2H), 1.40 (s,9H), log P (HCO2H): 3.62

Processes G and H

2-{3-[2-(1-{[3,5-Bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazol-4-yl]-4,5-dihydro-1,2-oxazol-5-yl}-3-fluorobenzaldehyde(I-17)

To a solution of tert-butyl4-{4-[5-(2-fluor-6-formylphenyl)-4,5-dihydro-1,2-oxazol-3-yl]-1,3-thiazol-2-yl}piperidine-1-carboxylate(112 mg) in dichloromethane was added dropwise, at 0° C., a 4 molarsolution of hydrogen chloride (4.0 eq.) in 1,4-dioxane. The reactionmixture was stirred at 0° C., and then gradually warmed to roomtemperature. After stirring for 5 hours, the solvent and excess hydrogenchloride were removed. This gave4-{4-[5-(2-fluoro-6-formylphenyl)-4,5-dihydro-1,2-oxazol-3-yl]-1,3-thiazol-2-yl}piperidiniumchloride (XII-10).

To a solution of [3,5-bis-(difluoromethyl)-1H-pyrazol-1-yl]acetic acid(58 mg) in dichloromethane (20 ml) were added, at 0° C., oxalyl chloride(94.5 mg) and one drop of N,N-dimethylformamide. The reaction mixturewas stirred at room temperature for 2 hours. The solvent and the excessreagent were removed under reduced pressure. The solid residue was againdissolved in dichloromethane (5 ml) and, at 0° C., added dropwise to asolution of4-{4-[5-(2-fluoro-6-formylphenyl)-4,5-dihydro-1,2-oxazol-3-yl]-1,3-thiazol-2-yl}piperidiniumchloride and triethylamine (5.0 eq.) in dichloromethane (15 ml). Thereaction mixture was stirred at room temperature overnight. Then it wasadmixed with concentrated sodium hydrogencarbonate solution, and theaqueous phase was removed and extracted with ethyl acetate. The combinedorganic phases were dried over sodium sulphate and concentrated.Purification by column chromatography gave2-{3-[2-(1-{[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazol-4-yl]-4,5-dihydro-1,2-oxazol-5-yl}-3-fluorobenzaldehyde(55 mg).

EXAMPLES

TABLE 1 (I)

In Table 1, the G group occurs especially in the specifications G3 andG4: G3 means G4 means: Ex. X R¹ G R² R³ R^(Tz) logp I-1 O H G3 phenyl HH 3.17^([b]); 3.11^([c]) I-2 O H G3 2,6-difluorophenyl H H 3.14^([b])I-3 O H G4 phenyl H 3.66^([b]) I-4 O Fluoro G3 2-fluorophenyl H H3.49^([b]) I-5 O Fluoro G3 phenyl H H 3.41^([b]) I-6 O Fluoro G32,6-difluorophenyl H H 3.43^([b]); 3.34^([c]) I-7 O H G3 2-acetylphenylH H 3.08^([b]) I-8 O H G3 3-acetylphenyl H H 2.78^([b]) I-9 O H G32-hyrdoxyphenyl H H 2.58^([a]); 2.6^([c]) I-10 O H G3 2-nitrophenyl H H3.19^([b]) I-11 O H G3 2-[(2-methoxyethoxy)methyl]phenyl H H 3.21^([b])I-12 O H G3 2-[(ethylsulphanyl)methyl]phenyl H H 3.9^([b]) I-13 O H G32-[(cyclopropylmethoxy)carbonyl]phenyl H H 3.92^([c]); 3.99^([b]) I-14 OH G3 2-(allyoxy)phenyl H H 3.63^([b]); 3.65^([c]) I-15 O H G33-(but-2-yn-1-yloxy)phenyl H H 3.33^([c]); 3.29^([a]) I-16 O H G32-(butoxymethyl)phenyl H H 4.24^([b]) I-17 O H G32-fluoro-6-formylphenyl H H 2.82^([c]); 2.92^([b]) I-18 O H G32-[(2-methylprop-2-en-1-yl)oxy]phenyl H H 3.96^([b]); 3.92^([c]) I-19 OH G3 2-(2-methoxyethoxy)phenyl H H 3.18^([c]); 3.26^([b]) I-20 O H G32-[(3-methylbut-2-en-1-yl)oxy]phenyl H H 4.19^([b]); 4.11^([c]) I-21 O HG3 3-(prop-2-yn-1-yloxy)phenyl H H 3.16^([c]); 3.24^([a]) I-22 O H G34-(prop-2-yn-1-yloxy)phenyl H H 3.14^([a]); 3.08^([c]) I-23 O H G33-formylphenyl H H 2.78^([b]) I-24 O H G3 2-(cyclohexylmethoxy)phenyl HH 4.9^([a]); 4.9^([c]) I-25 O H G3 2-(pent-2-yn-1-yloxy)phenyl H H3.91^([b]) I-26 O H G3 2-formylphenyl H H 2.98^([b]) I-27 O H G32-(cyclopropylcarbamoyl)phenyl H H 2.64^([b]) I-28 O H G33-(2-methoxyethoxy)phenyl H H 3.03^([b]); 3.04^([c]) I-29 O H G32-(but-2-yn-1-yloxy)-6-fluorophenyl H H 3.46^([a]); 3.42^([c]) I-30 O HG3 2-fluoro-6-(prop-2-yn-1-yloxy)phenyl H H 3.18^([a]); 3.15^([c]) I-31O H G4 2-formylphenyl H 3.25^([b]) I-32 O H G32-[(cyclohexylcarbanoyl)oxy]phenyl H H 4.27^([a]); 4.19^([c]) I-33 O HG3 2-[(cyclopropylcarbanoyl)oxy]phenyl H H 3.28^([c]); 3.34^([a]) I-34 OH G3 3-(pent-2-yn-1-yloxy)phenyl H H 3.74^([c]); 3.83^([a]) I-35 O H G32-(but-2-yn-1-yloxy)phenyl H H 3.55^([c]); 3.65^([a]) I-36 O H G32-[(3,3,3-trifluoropropanoyl)oxy]phenyl H H 9.43^([a]); 3.52^([c]) I-37O H G3 2-[(methylsulphonyl)amino]phenyl H H 2.51^([b]) I-38 O H G32-ethynylphenyl H H 3.36^([b]) I-39 O H G3 2-(prop-2-yn-1-yloxy)phenyl HH 3.23^([c]); 3.28^([a]) I-40 O H G3 4-[(methylsulphonyl)amino]phenyl HH 2.41^([b]) I-41 O H G3 2-aminophenyl H H 2.71^([c]); 2.7^([a]) I-42 OH G3 3-hydroxyphenyl H H 2.45^([c]); 2.43^([a]) I-43 O H G32-(methoxycarbonyl)phenyl H H 3.32^([b]) I-44 O H G32-(chloromethyl)phenyl H H 3.36^([b]) I-45 O H G32-(hydroxymethyl)phenyl H H 2.45^([b]) I-46 O H G32-(methoxycarbonyl)phenyl H Chloro 3.98^([b]) I-47 O H G34-(pent-2-yn-1-yloxy)phenyl H H 3.74^([c]); 3.76^([a]) I-48 O H G34-(but-2-yn-1-yloxy)phenyl H H 3.42^([c]); 3.43^([a]) I-49 O H G32-chloro-6-(prop-2-yn-1-yloxy)phenyl H H 3.5^([b]); 3.34^([c]) I-50 O HG3 2-chloro-6-(2-methoxyethoxy)phenyl H H 3.36^([b]) I-51 O H G32-(allyoxy)-6-chlorophenyl H H 3.71^([c]); 3.82^([b]) I-52 O H G32-[(2,2,2-trifluoroethoxy)methyl]phenyl H H 3.6^([c]); 3.4^([b]) I-53 OH G3 2-[(ethylsulphonyl)methyl]phenyl H H 2.76^([b]) I-54 O H G32-chloro-6-hydroxyphenyl H H 2.94^([b])

The log P values were determined according to EEC Directive 79/831 AnnexV.A8 by HPLC (High-Performance Liquid Chromatography) on reversed-phasecolumns (C 18) by the following methods:

^([a]) The determination is effected in the acidic range at pH 2.3 using0.1% aqueous phosphoric acid and acetonitrile as eluents; lineargradient from 10% acetonitrile to 95% acetonitrile.

^([b]) The LC-MS determination in the acidic range is effected at pH 2.7using 0.1% aqueous formic acid and acetonitrile (contains 0.1% formicacid) as eluents; linear gradient from 10% acetonitrile to 95%acetonitrile.

^([c]) The LC-MS determination in the neutral range is effected at pH7.8 using 0.001 molar aqueous ammonium hydrogencarbonate solution andacetonitrile as eluents; linear gradient from 10% acetonitrile to 95%acetonitrile.

The calibration is effected with unbranched alkan-2-ones (having 3 to 16carbon atoms) with known log P values (determination of the log P valuesusing the retention times by linear interpolation between two successivealkanones).

The lambda-max values were determined in the maxima of thechromatographic signals using the UV spectra from 200 nm to 400 nm.

NMR Data of Selected Examples

Ex. NMR Data I-1 ¹H NMR: δ_(ppm): 1.63 (m, 1H), 1.79 (m, 1H), 2.18-2.05(m, 2H), 2.88 (m, 1H), 3.42-3.20 (m, 3H), 3.87 (dd, 1H), 3.98 (m, 1H),4.32 (m, 1H), 5.35 (bs, 2H), 5.72 (dd, 1H), 6.85 (s, 1H), 6.97 (t, 1H),7.14 (t, 1H), 7.40-7.30 (m, 5H), 7.97 (s, 1H) I-2 ¹H NMR: δ_(ppm): 1.58(m, 1H), 1.83 (m, 1H), 2.18-2.07 (m, 2H), 2.85 (m, 1H), 3.25 (m, 1H),3.41 (m, 1H), 3.52 (dd, 1H), 3.90 (dd, 1H), 3.98 (m, 1H), 4.36 (m, 1H),5.35 (d, 1H), 5.47 (d, 1H), 6.01 (dd, 1H), 6.90 (s, 1H), 7.02 (t, 1H),7.18 (t, 1H), 7.19-7.12 (m, 2H), 7.50 (m, 1H), 8.03 (s, 1H) I-3 ¹H NMR:δ_(ppm): 1.66 (m, 1H), 1.85 (m, 1H), 2.22-2.10 (m, 2H), 2.88 (dd, 1H),3.50-3.45 (m, 2H), 4.00 (d, 1H), 4.39 (d, 1H), 5.37 (d, 1H), 5.45 (d,1H), 6.91 (s, 1H), 7.03 (t, 1H), 7.19 (t, 1H), 7.44 (s, 1H), 7.60-7.53(m, 3H), 7.96 (dd, 2H), 8.23 (s, 1H) I-4 ¹H NMR: δ_(ppm): 2.45-2.05 (m,4H), 3.10 (m, 1H), 3.44 (dd, 1H), 3.47 (m, 1H), 3.98-3.90 (m, 2H), 4.28(m, 1H), 5.40 (d, 1H), 5.51 (d, 1H), 5.94 (dd, 1H), 6.91 (s, 1H), 7.03(t, 1H), 7.18 (t, 1H), 7.32- 7.20 (m, 2H), 7.48-7.38 (m, 2H), 8.24 (s,1H) I-5 ¹H NMR: δ_(ppm): 2.45-2.05 (m, 4H), 3.11 (m, 1H), 3.38 (dd, 1H),3.48 (m, 1H), 3.95-3.86 (m, 2H), 4.26 (m, 1H), 5.39 (d, 1H), 5.50 (d,1H), 5.76 (dd, 1H), 6.91 (s, 1H), 7.03 (t, 1H), 7.18 (t, 1H), 7.42- 7.33(m, 5H), 8.22 (s, 1H) I-6 ¹H NMR (CD₃CN): δ_(ppm): 2.50-2.10 (m, 4H),3.18 (m, 1H), 3.55 (m, 1H), 3.59 (dd, 1H), 3.89-3.78 (m, 2H), 4.36 (m,1H), 5.22 (d, 1H), 5.29 (d, 1H), 6.07 (dd, 1H), 6.79 (t, 1H), 6.83 (s,1H), 6.91 (t, 1H), 7.07-6.99 (m, 2H), 7.42 (m, 1H), 7.88 (s, 1H)

The chemical NMR shifts in ppm were measured at 400 MHz, unless statedotherwise in the solvent DMSO-d₆ with tetramethylsilane as the internalstandard.

The following abbreviations describe the signal splitting:

b=broad, s=singlet d=doublet, t=triplet, q=quadruplet, m=multiplet

NMR Data of Selected Examples

NMR Peak List Procedure

The 1H NMR data of selected examples are noted in the form of 1H NMRpeak lists. For each signal peak, the δ value in ppm and the signalintensity are listed in brackets.

Ex. I-8, Solvent: DMSO-d₆ 8.0369 (5.64); 7.953 (3.33); 7.9506 (3.17);7.9343 (1.15); 7.9312 (1.42); 7.6713 (1.04); 7.652 (1.46); 7.5832(1.24); 7.5643 (1.87); 7.5446 (0.75); 7.307 (1); 7.1737 (2.29); 7.1587(1.17); 7.0404 (1.14); 7.0226 (2.57); 6.9004 (2.47); 6.8868 (1.32);5.8661 (0.82); 5.8458 (1); 5.8389 (0.98); 5.8188 (0.86); 5.4508 (0.47);5.408 (1.81); 5.3671 (1.73); 5.3247 (0.46); 4.3643 (0.54); 4.33 (0.57);4.0573 (0.63); 4.0395 (1.85); 4.0217 (1.88); 4.0039 (0.73); 3.984(0.53); 3.9632 (1.19); 3.9508 (0.62); 3.9359 (1.24); 3.92 (1.23); 3.8927(1.02); 3.4369 (1.22); 3.4167 (1.62); 3.4071 (0.58); 3.3936 (1.63);3.3881 (1.26); 3.3735 (1.77); 3.3194 (308.6); 3.2418 (0.85); 2.891(0.55); 2.8724 (0.42); 2.8441 (0.72); 2.8149 (0.43); 2.7325 (0.4);2.6704 (0.34); 2.5949 (16); 2.5522 (0.37); 2.5404 (0.69); 2.5235 (1.54);2.5102 (19.34); 2.5059 (35.33); 2.5015 (45.46); 2.4971 (31.98); 2.4929(15.8); 2.3283 (0.36); 2.1377 (0.55); 2.1018 (1.05); 2.0693 (0.92);1.9871 (8.04); 1.8117 (0.49); 1.7902 (0.44); 1.5915 (0.45); 1.5827(0.5); 1.5611 (0.46); 1.5519 (0.44); 1.398 (2.53); 1.2365 (0.34); 1.193(2.23); 1.1752 (4.38); 1.1575 (2.15); 0.0078 (0.39); −0.0002 (7.25);−0.0082 (0.34) Ex. I-9, Solvent: DMSO-d₆ 9.7066 (7.97); 8.0287 (0.34);8.0022 (10.13); 7.3071 (1.98); 7.2167 (2.69); 7.1976 (2.79); 7.1737(4.5); 7.1591 (2.52); 7.1535 (1.76); 7.1494 (1.48); 7.1338 (2.64);7.1147 (1.75); 7.1106 (1.5); 7.0405 (2.26); 7.0231 (4.87); 6.8986(5.15); 6.8873 (2.7); 6.8638 (3.65); 6.8438 (3.23); 6.8125 (1.98);6.7939 (3.39); 6.7754 (1.61); 5.8556 (1.76); 5.8368 (2.06); 5.8279 (2);5.8092 (1.77); 5.4492 (0.98); 5.4074 (3.65); 5.3673 (3.74); 5.3251(0.97); 4.3592 (1.22); 4.3252 (1.24); 4.0571 (1.37); 4.0393 (3.86);4.0215 (3.89); 4.0038 (1.48); 3.9781 (1.2); 3.9449 (1.26); 3.8484 (1.8);3.8204 (2.02); 3.8055 (2.29); 3.7778 (1.96); 3.4036 (1.2); 3.3939 (1.1);3.3846 (1.56); 3.3756 (2.26); 3.3661 (1.82); 3.3464 (2.39); 3.3065(242.8); 3.2791 (3.62); 3.2656 (2.17); 3.2552 (2.76); 3.2364 (2.8);2.8685 (0.84); 2.8404 (1.49); 2.8107 (0.85); 2.6692 (0.58); 2.6648(0.47); 2.5392 (1.55); 2.5046 (63.17); 2.5003 (76.51); 2.4964 (53.38);2.3316 (0.41); 2.327 (0.5); 2.1301 (1.13); 2.0982 (2.27); 2.0692 (1.31);1.9869 (16); 1.8411 (0.47); 1.8172 (0.97); 1.811 (1.01); 1.7889 (0.92);1.759 (0.37); 1.6137 (0.42); 1.6042 (0.48); 1.5829 (0.94); 1.5746(0.98); 1.5538 (0.95); 1.5452 (0.87); 1.5238 (0.37); 1.3981 (0.73);1.1928 (4.43); 1.175 (8.57); 1.1572 (4.18); −0.0002 (2.26) Ex. I-10,Solvent: DMSO-d₆ 9.9026 (0.53); 8.7786 (0.82); 8.6473 (0.5); 8.4336(0.4); 8.1699 (2.2); 8.1671 (2.25); 8.1494 (2.4); 8.1466 (2.37); 8.0449(8.69); 7.8303 (0.96); 7.8276 (0.99); 7.81 (2.12); 7.7925 (1.53); 7.7897(1.47); 7.6818 (2.46); 7.665 (1.83); 7.6621 (1.84); 7.6401 (1.46);7.6366 (1.32); 7.6191 (2.13); 7.6013 (1.16); 7.5979 (1.04); 7.305(1.64); 7.1717 (3.75); 7.1581 (1.97); 7.0384 (1.89); 7.0221 (4.3);6.8984 (4.07); 6.8862 (2.33); 6.2689 (1.29); 6.2533 (1.45); 6.2409(1.46); 6.2251 (1.32); 5.7475 (1.13); 5.4471 (0.79); 5.4048 (2.82);5.365 (2.84); 5.3233 (0.77); 4.3558 (0.94); 4.3252 (1.02); 4.3078(0.59); 4.2898 (0.36); 4.1407 (1.39); 4.1124 (1.59); 4.0965 (1.79);4.0684 (1.57); 4.0573 (1.34); 4.0395 (3.7); 4.0217 (3.75); 4.0039(1.38); 3.9768 (0.91); 3.9436 (0.96); 3.4422 (1.76); 3.4264 (1.82);3.4113 (0.58); 3.3982 (2.02); 3.3825 (2.38); 3.3737 (1.46); 3.3641(0.94); 3.3541 (0.78); 3.3445 (1.03); 3.3352 (0.97); 3.3023 (178.37);3.2798 (2.37); 3.2613 (1.61); 3.2312 (0.85); 3.0381 (0.37); 2.8638(0.7); 2.8507 (0.64); 2.8327 (1.16); 2.8038 (0.66); 2.6696 (0.41);2.6649 (0.32); 2.5396 (0.72); 2.5092 (23.41); 2.5049 (43.1); 2.5005(56.19); 2.4961 (40.14); 2.4918 (20.08); 2.3319 (0.33); 2.3275 (0.41);2.1465 (0.37); 2.1243 (0.96); 2.0891 (1.7); 2.0702 (0.87); 2.0549(0.95); 1.9871 (16); 1.8344 (0.43); 1.8118 (0.79); 1.8063 (0.8); 1.7814(0.74); 1.6064 (0.38); 1.5981 (0.43); 1.5768 (0.77); 1.5683 (0.78);1.5476 (0.73); 1.5382 (0.67); 1.3977 (1.14); 1.3202 (0.35); 1.3026(0.69); 1.2848 (0.36); 1.2363 (0.38); 1.193 (4.46); 1.1752 (8.83);1.1574 (4.38); 0.0596 (1.49); −0.0002 (3.18) Ex. I-11, Solvent: CD₃CN7.6716 (4.88); 7.4701 (1.37); 7.4579 (1.37); 7.4558 (1.26); 7.3757(0.71); 7.366 (1.87); 7.3544 (2); 7.3193 (1.14); 7.3079 (1.33); 7.2958(0.49); 6.9878 (1.11); 6.898 (2.29); 6.8776 (1.16); 6.8311 (2.32);6.8083 (1.15); 6.7866 (2.38); 6.6957 (1.19); 5.9944 (1.02); 5.98 (1.14);5.9761 (1.13); 5.9617 (1.04); 5.2629 (0.75); 5.2346 (2.39); 5.203 (2.4);5.1748 (0.78); 4.6614 (1.85); 4.6422 (2.48); 4.534 (2.57); 4.5148(1.92); 4.4734 (0.56); 4.4508 (0.59); 4.0646 (0.52); 4.0527 (0.52);3.9375 (1.16); 3.919 (1.47); 3.9088 (1.74); 3.8903 (1.81); 3.633 (0.33);3.6312 (0.34); 3.622 (0.93); 3.6155 (1.02); 3.6127 (1.16); 3.6068(1.68); 3.6003 (1.56); 3.593 (1.26); 3.5821 (0.5); 3.575 (0.41); 3.5279(2.27); 3.5209 (2.9); 3.5178 (1.41); 3.5142 (1.25); 3.5114 (1.13);3.3636 (0.49); 3.3509 (0.52); 3.3445 (1); 3.3381 (0.53); 3.3254 (0.53);3.3069 (0.46); 3.3023 (0.6); 3.2958 (16); 3.283 (1.39); 3.2669 (1.45);3.2594 (0.49); 3.2527 (1.3); 3.2383 (1.21); 3.224 (1.19); 2.8775 (0.38);2.873 (0.42); 2.8557 (0.73); 2.8523 (0.75); 2.8351 (0.45); 2.8306(0.41); 2.201 (69.88); 2.1761 (1.1); 2.1451 (0.6); 2.1232 (0.61); 1.9733(2.23); 1.9665 (1.21); 1.9583 (0.58); 1.9504 (8.08); 1.9463 (14.95);1.9422 (21.76); 1.9381 (14.82); 1.934 (7.55); 1.8641 (0.53); 1.8576(0.54); 1.8431 (0.5); 1.8364 (0.52); 1.6993 (0.54); 1.6927 (0.57);1.6786 (0.53); 1.672 (0.51); 1.4358 (0.96); 1.2157 (0.58); 1.2039(1.15); 1.192 (0.58); 1.1138 (0.43); −0.0002 (3.37) Ex. I-12, Solvent:DMSO-d₆ 8.0249 (9.55); 8.018 (0.5); 7.3706 (1.21); 7.3647 (1.69); 7.348(2.04); 7.3268 (1.05); 7.3187 (1.26); 7.3109 (2.51); 7.3054 (3.71);7.3007 (3.98); 7.2948 (1.66); 7.2903 (3.15); 7.2842 (4.3); 7.2772(1.28); 7.2741 (1.16); 7.2685 (1.2); 7.2553 (0.42); 7.1752 (3.67);7.1646 (1.82); 7.042 (1.78); 7.0286 (4.12); 6.9069 (3.51); 6.8928 (2);6.0983 (1.32); 6.0778 (1.61); 6.0706 (1.59); 6.0501 (1.38); 5.4543(0.81); 5.4117 (2.73); 5.37 (2.71); 5.3271 (0.8); 4.3626 (0.8); 4.3301(0.86); 4.0165 (1.37); 3.9887 (2.07); 3.9734 (2.27); 3.9457 (2.23);3.9192 (1.95); 3.8865 (3.67); 3.8314 (3.75); 3.7985 (1.95); 3.5567(0.35); 3.5284 (0.34); 3.5202 (0.37); 3.5117 (0.33); 3.4896 (0.71);3.4738 (0.77); 3.4573 (1.27); 3.4434 (1.57); 3.4376 (1.71); 3.3605(1918.14); 3.3154 (7.54); 3.2944 (5.31); 3.2716 (3.59); 3.2513 (2.77);3.2419 (1.37); 3.236 (1.44); 3.1808 (0.62); 3.153 (0.39); 3.1441 (0.39);3.1275 (0.39); 3.1088 (0.34); 3.0997 (0.34); 3.0366 (0.38); 2.8643(0.67); 2.8337 (1.11); 2.8064 (0.66); 2.6818 (0.5); 2.6773 (0.95);2.6728 (1.31); 2.6682 (0.99); 2.6636 (0.52); 2.5428 (0.86); 2.5258(3.63); 2.5127 (71.69); 2.5082 (143.99); 2.5036 (190.58); 2.499(138.34); 2.4945 (68.05); 2.4728 (8.16); 2.4544 (2.6); 2.3396 (0.51);2.3349 (0.97); 2.3304 (1.33); 2.3257 (0.98); 2.3213 (0.52); 2.1309(0.76); 2.0983 (1.52); 2.0724 (2.06); 2.0645 (0.89); 1.9887 (1.18);1.8357 (0.37); 1.814 (0.68); 1.8056 (0.73); 1.7838 (0.68); 1.7757(0.65); 1.7534 (0.32); 1.6126 (0.35); 1.6031 (0.37); 1.5818 (0.68);1.5728 (0.74); 1.5511 (0.72); 1.5426 (0.67); 1.5216 (0.33); 1.4083(0.58); 1.4018 (1.38); 1.3975 (3.65); 1.2468 (0.49); 1.2348 (1.13);1.2098 (7.77); 1.1915 (16); 1.1815 (0.75); 1.173 (7.39); 1.1632 (0.52);1.1571 (0.51); −0.0002 (2.47) Ex. I-13, Solvent: DMSO-d₆ 9.6057 (0.54);8.2467 (0.32); 8.0242 (16); 7.9807 (4.9); 7.9789 (5.09); 7.9613 (5.33);7.9594 (5.41); 7.6688 (1.95); 7.651 (4.61); 7.6335 (3.5); 7.6311 (3.38);7.5754 (6.21); 7.5559 (3.99); 7.4997 (3.02); 7.4806 (4.85); 7.462(2.37); 7.4596 (2.24); 7.4309 (0.6); 7.3103 (3.18); 7.2985 (1.58);7.2187 (0.36); 7.1926 (0.81); 7.1769 (6.82); 7.1667 (4.6); 7.1588(1.71); 7.0569 (1.42); 7.0438 (3.68); 7.0306 (7.77); 6.9685 (1.07);6.9211 (1.09); 6.9073 (8.56); 6.895 (4.7); 6.8611 (0.87); 6.3432 (2.94);6.3268 (3.57); 6.3227 (2.96); 6.3155 (3.57); 6.3069 (2.32); 6.2992(3.1); 5.7558 (9.53); 5.4535 (1.72); 5.4109 (6.13); 5.3724 (6.29);5.3547 (1.01); 5.3299 (1.91); 5.3073 (2.85); 5.0692 (0.44); 4.3568(1.99); 4.3242 (2.46); 4.2663 (0.93); 4.2552 (1.08); 4.2435 (0.97);4.2242 (0.45); 4.2144 (0.37); 4.1905 (0.9); 4.1795 (1.43); 4.1621(8.14); 4.1571 (8.22); 4.1436 (8.48); 4.1391 (7.89); 4.1101 (1.18);4.0779 (2.79); 4.0499 (3.03); 4.0339 (3.39); 4.006 (3); 3.9757 (1.91);3.9412 (2.17); 3.9051 (0.41); 3.7197 (0.55); 3.71 (0.93); 3.7025 (1.42);3.6921 (1.76); 3.6756 (2.52); 3.6662 (2); 3.6626 (1.99); 3.6539 (1.21);3.3958 (1.33); 3.3856 (1.23); 3.3755 (1.92); 3.3669 (3.52); 3.3372(183.1); 3.2889 (2.29); 3.2593 (5.73); 3.2434 (4.25); 3.2277 (2.14);3.2156 (3.76); 3.1994 (3.23); 3.0397 (0.96); 2.8529 (1.59); 2.8294(2.58); 2.7993 (1.59); 2.5085 (31.73); 2.5042 (40.36); 2.5006 (31.19);2.1191 (1.74); 2.0847 (3.76); 2.0484 (2.3); 1.9901 (0.75); 1.9116(0.53); 1.8388 (0.7); 1.8288 (0.81); 1.8077 (1.59); 1.8 (1.7); 1.7771(1.66); 1.7691 (1.56); 1.7472 (0.89); 1.6014 (0.74); 1.5924 (0.93);1.5708 (1.64); 1.5626 (1.79); 1.5404 (1.69); 1.532 (1.7); 1.5103 (0.79);1.5016 (0.72); 1.4187 (0.45); 1.396 (0.45); 1.3124 (0.58); 1.3056(0.97); 1.2937 (1.9); 1.2858 (1.89); 1.2822 (1.76); 1.2741 (2.96);1.2624 (2.15); 1.2554 (2.32); 1.2434 (1.7); 1.235 (2.16); 1.1935 (0.39);1.1757 (0.59); 1.1579 (0.48); 1.145 (0.41); 0.6187 (1.63); 0.6077(6.47); 0.6032 (7.52); 0.5875 (6.99); 0.5833 (7.15); 0.5745 (2.7); 0.555(0.38); 0.4071 (2.63); 0.3943 (8.38); 0.385 (8.14); 0.3822 (8.4); 0.371(2.61); −0.0002 (6.9) Ex. I-14, Solvent: DMSO-d₆ 8.0236 (0.7); 8.0022(16); 7.3308 (0.39); 7.31 (4.8); 7.3047 (5.83); 7.294 (5.45); 7.2907(5.94); 7.2867 (3.62); 7.2762 (2.96); 7.272 (1.65); 7.2604 (0.35);7.1711 (6.22); 7.1574 (3.08); 7.098 (0.36); 7.0613 (4.54); 7.0385(5.81); 7.0214 (7.05); 6.9759 (2.57); 6.9556 (4.33); 6.9388 (2.08);6.8984 (6); 6.8855 (3.41); 6.0801 (0.82); 6.0676 (1.68); 6.0539 (1.23);6.041 (1.97); 6.0369 (1.1); 6.0285 (1.1); 6.0243 (2.09); 6.0112 (1.46);5.9978 (1.99); 5.9853 (0.98); 5.9175 (2.25); 5.8995 (2.61); 5.8897(2.54); 5.8715 (2.27); 5.7458 (1.02); 5.4481 (1.46); 5.4408 (1.86);5.4364 (3.92); 5.4321 (3.92); 5.4278 (1.69); 5.406 (4.76); 5.3977(2.07); 5.3931 (3.63); 5.3888 (3.51); 5.3846 (1.53); 5.3636 (4.56);5.3206 (1.24); 5.249 (1.58); 5.2453 (3.51); 5.2413 (3.35); 5.2224(1.44); 5.2188 (3.21); 5.2148 (3.09); 4.6659 (0.44); 4.6531 (0.55);4.6319 (5.25); 4.6273 (5.61); 4.6235 (4.66); 4.6195 (5.22); 4.6149(4.69); 4.5934 (0.44); 4.5807 (0.37); 4.3587 (1.45); 4.3249 (1.48);4.0571 (1.18); 4.0393 (3.19); 4.0215 (3.25); 4.0036 (1.32); 3.9797(1.39); 3.943 (1.53); 3.8883 (2.58); 3.8602 (2.89); 3.8454 (3.27);3.8174 (2.78); 3.6096 (0.34); 3.5899 (0.32); 3.581 (0.32); 3.5439(0.41); 3.4592 (0.77); 3.4119 (2.02); 3.4044 (2.54); 3.384 (3.45);3.3751 (4.96); 3.3656 (4.99); 3.3168 (1799.9); 3.2952 (11.71); 3.2702(5.7); 3.2455 (3.61); 3.2275 (3.65); 2.8652 (1); 2.8349 (1.7); 2.8071(0.97); 2.6745 (0.73); 2.6699 (0.91); 2.6653 (0.7); 2.54 (1.38); 2.5097(53.59); 2.5054 (99.23); 2.5009 (128.95); 2.4965 (89.43); 2.4921 (43.1);2.4526 (0.36); 2.3323 (0.63); 2.3277 (0.83); 2.3232 (0.59); 2.1295(1.28); 2.0945 (2.65); 2.069 (2.03); 2.0582 (1.46); 1.9868 (13.72);1.9081 (0.4); 1.8418 (0.51); 1.8321 (0.56); 1.8033 (1.16); 1.7809(1.08); 1.7503 (0.44); 1.6001 (0.58); 1.5701 (1.17); 1.5485 (1.11);1.5401 (1.07); 1.5208 (0.44); 1.2365 (0.93); 1.1929 (3.85); 1.1751(7.58); 1.1573 (3.78); −0.0002 (1.21) Ex. I-15, Solvent: DMSO-d₆ 19.3402(0.52); 18.635 (0.51); 16.0748 (0.5); 15.6162 (0.51); 10.962 (0.5);8.7762 (1.87); 8.0216 (12.7); 7.338 (1.94); 7.3172 (3.86); 7.3056(2.78); 7.2972 (2.3); 7.1726 (5.32); 7.158 (2.83); 7.1274 (0.51); 7.0389(2.79); 7.0219 (6.63); 6.9886 (2.92); 6.9713 (5.97); 6.9679 (5.9);6.9426 (2.25); 6.9374 (1.8); 6.9239 (2.13); 6.9204 (2.16); 6.916 (1.65);6.8985 (5.7); 6.886 (3.09); 5.7459 (3.25); 5.7257 (1.7); 5.7056 (2.21);5.6986 (2.02); 5.6795 (1.74); 5.4503 (1.08); 5.4065 (3.97); 5.3662(4.29); 5.3405 (0.56); 5.3239 (1.22); 4.9643 (0.56); 4.8644 (0.94);4.7451 (2.83); 4.7392 (6.89); 4.7334 (6.77); 4.3597 (1.41); 4.3248(1.57); 4.2932 (0.57); 4.254 (0.53); 4.0647 (0.54); 4.0492 (0.56);4.0238 (0.77); 4.0151 (0.8); 3.9841 (1.58); 3.9491 (1.86); 3.9194(0.74); 3.9007 (1.97); 3.873 (2.14); 3.8577 (2.62); 3.8301 (2.25);3.8081 (0.75); 3.7756 (0.67); 3.7622 (0.75); 3.7313 (0.88); 3.681(0.88); 3.6589 (0.97); 3.6381 (1.03); 3.6044 (1.02); 3.6014 (1.13);3.5919 (1.14); 3.5702 (1.18); 3.5265 (1.44); 3.5016 (1.8); 3.488 (1.94);3.4506 (2.67); 3.4442 (2.95); 3.3911 (8.54); 3.3836 (9); 3.3714 (11.9);3.312 (9031.04); 3.2888 (42.26); 3.2562 (4.61); 3.2375 (2.49); 3.2002(0.97); 2.8742 (1.14); 2.8423 (1.67); 2.8136 (1.06); 2.7557 (0.71);2.7114 (0.6); 2.689 (0.92); 2.6739 (5.79); 2.6696 (7.64); 2.6649 (5.69);2.66 (2.96); 2.6526 (1.24); 2.6439 (1.02); 2.6164 (2.23); 2.5395(10.71); 2.5226 (33.05); 2.5094 (449.88); 2.505 (830.26); 2.5005(1078.36); 2.4961 (734.7); 2.4916 (343.72); 2.4181 (0.66); 2.3318 (5.5);2.3272 (7.16); 2.3226 (5.11); 2.318 (2.55); 2.1526 (0.69); 2.1332(1.28); 2.1035 (2.53); 2.0689 (2.9); 1.8059 (8.69); 1.8001 (16); 1.7943(7.63); 1.7485 (0.63); 1.6193 (0.53); 1.583 (1.21); 1.5655 (0.81);1.5568 (1.11); 1.3515 (0.62); 1.2977 (0.67); 1.2593 (1.19); 1.2361(3.44); 1.1523 (0.5); 1.1082 (0.83); 1.0908 (1.05); 0.8911 (0.5); 0.8613(1.13); 0.0079 (2.63); −0.0002 (60.11); −0.0085 (2.24); −2.4058 (0.5)Ex. I-16, Solvent: DMSO-d₆ 8.0088 (10.55); 7.3947 (1.35); 7.3898 (1.87);7.3842 (1.49); 7.3778 (2.38); 7.3724 (3.88); 7.3657 (3.51); 7.3594(1.85); 7.3461 (2.79); 7.3421 (1.98); 7.3275 (3.4); 7.3219 (2.58);7.3096 (2.42); 7.3051 (2.79); 7.2924 (0.86); 7.2872 (0.72); 7.1726(3.67); 7.1632 (1.95); 7.0442 (0.73); 7.0394 (1.84); 7.0272 (4.12);6.9623 (0.49); 6.9066 (3.51); 6.8914 (2.05); 5.9844 (1.31); 5.9645(1.63); 5.9566 (1.58); 5.9367 (1.39); 5.6319 (0.74); 5.4476 (0.7); 5.405(2.7); 5.3699 (2.69); 5.3272 (0.73); 5.2701 (0.39); 4.5849 (1.61);4.5554 (3.94); 4.5218 (4.01); 4.4922 (1.69); 4.3564 (0.76); 4.3237(0.85); 4.1907 (0.6); 4.0563 (0.83); 4.0385 (2.51); 4.0207 (2.6); 4.0029(0.91); 3.9773 (0.73); 3.9441 (0.8); 3.9205 (1.41); 3.8926 (1.52);3.8773 (1.73); 3.8495 (1.41); 3.5021 (0.56); 3.4856 (1.17); 3.4788(1.82); 3.4626 (4.53); 3.4471 (4.64); 3.4403 (1.69); 3.4311 (2.29);3.424 (2.09); 3.4047 (3.38); 3.3648 (663.23); 3.2947 (3.3); 3.2745(2.64); 3.2675 (1.8); 3.2514 (2.31); 3.2316 (2.44); 3.1937 (0.37);3.1863 (0.35); 2.8676 (0.6); 2.8366 (1.04); 2.8103 (0.62); 2.6779(0.33); 2.6733 (0.45); 2.6687 (0.35); 2.5265 (1.15); 2.5133 (25.22);2.5088 (51.37); 2.5042 (68.85); 2.4996 (50.01); 2.495 (24.56); 2.3354(0.37); 2.3309 (0.49); 2.3263 (0.36); 2.1286 (0.71); 2.0973 (1.47);2.0725 (0.98); 2.0611 (0.9); 2.0228 (1.11); 2.0072 (0.51); 1.9889(11.5); 1.9102 (1.26); 1.8302 (0.37); 1.8086 (0.67); 1.8007 (0.71);1.7787 (0.69); 1.7706 (0.64); 1.7491 (0.34); 1.6148 (0.38); 1.6044(0.43); 1.5847 (0.75); 1.5742 (0.87); 1.5686 (0.94); 1.5648 (0.89);1.5508 (2.22); 1.5482 (2.2); 1.5434 (1.71); 1.5344 (2.8); 1.5304 (2.52);1.5181 (1.67); 1.513 (3.06); 1.4965 (1.43); 1.4786 (0.59); 1.462 (0.56);1.4549 (0.41); 1.4407 (0.4); 1.3831 (0.68); 1.3645 (2.01); 1.3454(3.11); 1.3266 (3.26); 1.3086 (2.13); 1.2903 (0.88); 1.2813 (0.59);1.235 (2.24); 1.2102 (0.51); 1.2011 (0.58); 1.1929 (3.68); 1.1751(6.89); 1.1692 (0.96); 1.1573 (3.46); 1.1119 (0.33); 0.8923 (7.76);0.8739 (16); 0.8554 (7.42); 0.8433 (1.11); 0.8357 (1); −0.0002 (4.51)Ex. I-17, Solvent: DMSO-d₆ 10.2605 (6.56); 9.8996 (1.37); 8.6648 (1.24);8.048 (14.68); 7.7701 (2.71); 7.7681 (2.95); 7.7574 (3.7); 7.7553(3.67); 7.6819 (1.07); 7.6733 (1.16); 7.6685 (1.93); 7.6601 (1.93);7.6554 (1.23); 7.647 (1.1); 7.6113 (1.52); 7.6095 (1.53); 7.5978 (1.16);7.5957 (1.23); 7.5931 (1.73); 7.5911 (1.61); 7.5794 (1.09); 7.5774(1.07); 7.3707 (0.39); 7.282 (0.85); 7.2731 (1.85); 7.1934 (0.5); 7.1845(4.41); 7.1399 (0.46); 7.1277 (2.02); 7.096 (2.12); 7.0495 (1.09);7.0373 (5.43); 6.9593 (0.54); 6.947 (2.39); 6.9132 (4.67); 6.5802(1.51); 6.5631 (1.94); 6.5438 (1.51); 5.7615 (16); 5.4563 (1.4); 5.4278(3.17); 5.3792 (3.33); 5.3508 (1.46); 5.0918 (0.47); 4.3659 (1.01);4.3437 (1.03); 4.0459 (1.09); 4.0341 (3.28); 4.0222 (3.3); 4.0104(1.11); 3.979 (1.53); 3.959 (1.77); 3.9561 (1.57); 3.9502 (1.29); 3.9471(1.24); 3.9273 (1.05); 3.5858 (1.32); 3.568 (1.64); 3.5574 (1.16);3.5395 (1.13); 3.4304 (0.6); 3.4237 (0.94); 3.417 (0.75); 3.4108 (1.14);3.4046 (1.86); 3.3984 (1.29); 3.392 (1.08); 3.3854 (1.5); 3.3488(364.36); 3.3255 (4.74); 3.2936 (0.88); 3.2736 (1.38); 3.2551 (0.76);3.0367 (0.34); 2.8638 (0.74); 2.8483 (1.28); 2.8264 (0.74); 2.6179(0.66); 2.6149 (0.95); 2.6119 (0.65); 2.5426 (0.66); 2.5242 (1.66);2.5211 (2.12); 2.518 (2.39); 2.5092 (54.14); 2.5062 (120.28); 2.5031(167.97); 2.5001 (118.69); 2.497 (50.51); 2.3903 (0.58); 2.3873 (0.88);2.3842 (0.6); 2.1466 (0.86); 2.1274 (1.02); 2.1072 (0.92); 2.0877(0.93); 2.0768 (1.48); 1.99 (14.99); 1.9096 (0.4); 1.8457 (0.37); 1.8257(0.8); 1.8052 (0.76); 1.6076 (0.34); 1.5888 (0.75); 1.5688 (0.77); 1.234(0.57); 1.1862 (4.33); 1.1744 (9.3); 1.1626 (4.08); 1.0551 (0.32);0.0053 (1.57); −0.0002 (50.67); −0.0057 (1.48) Ex. I-18, Solvent:DMSO-d₆ 8.012 (15.01); 7.3025 (4.08); 7.2994 (2.15); 7.2909 (4.11);7.2897 (4.25); 7.2889 (4.36); 7.2869 (2.41); 7.2792 (2.16); 7.2763(1.24); 7.2679 (1.71); 7.1793 (4.09); 7.1258 (1.87); 7.0908 (1.96);7.0511 (2.91); 7.0499 (3.08); 7.0452 (0.57); 7.0353 (7.48); 6.9669(1.77); 6.9656 (1.74); 6.9545 (3.16); 6.9532 (3.28); 6.945 (2.37);6.9422 (1.81); 6.9408 (1.62); 6.9111 (4.11); 5.9209 (1.7); 5.9091(1.96); 5.9025 (1.84); 5.8905 (1.71); 5.7615 (16); 5.4504 (1.42); 5.422(3.14); 5.3707 (3.11); 5.3424 (1.42); 5.0906 (3.19); 5.0894 (3.21);4.9454 (3.14); 4.5462 (0.76); 4.5248 (3.65); 4.5148 (3.71); 4.4932(0.75); 4.3533 (0.93); 4.3316 (0.95); 4.0341 (0.38); 4.0223 (0.37);3.9698 (0.85); 3.9473 (0.92); 3.8827 (1.89); 3.8642 (2.31); 3.8544(2.45); 3.8359 (1.99); 3.5679 (1.49); 3.3996 (0.42); 3.3932 (0.79);3.3869 (0.55); 3.3804 (0.9); 3.3737 (1.81); 3.3692 (1.06); 3.3674(1.15); 3.3488 (538.95); 3.3251 (3.75); 3.287 (2.31); 3.2751 (2.72);3.2586 (3.24); 3.2467 (2.29); 3.238 (0.74); 3.2337 (0.58); 2.8506(0.55); 2.8466 (0.66); 2.826 (1.16); 2.8083 (0.68); 2.618 (0.39); 2.6149(0.53); 2.6119 (0.39); 2.5242 (0.7); 2.5211 (0.9); 2.518 (0.85); 2.5092(28); 2.5062 (63.2); 2.5031 (87.71); 2.5001 (61.35); 2.497 (26.88);2.3904 (0.38); 2.3873 (0.52); 2.3842 (0.36); 2.1173 (0.79); 2.0956(0.92); 2.0767 (1.37); 2.0573 (0.87); 1.99 (1.75); 1.8163 (0.4); 1.8021(0.77); 1.7964 (0.99); 1.7845 (15.03); 1.762 (0.35); 1.563 (0.72);1.5563 (0.76); 1.5427 (0.73); 1.5361 (0.69); 1.2335 (0.41); 1.1862(0.49); 1.1744 (0.98); 1.1625 (0.49); 0.0052 (0.56); −0.0002 (19.67);−0.0058 (0.48) Ex. I-19, Solvent: DMSO-d₆ 7.9976 (2.12); 7.9829 (16);7.3208 (2.15); 7.3167 (3.02); 7.3041 (7.32); 7.2999 (8.68); 7.2813(7.15); 7.2609 (0.49); 7.2412 (0.34); 7.2375 (0.35); 7.1713 (7.18);7.1576 (3.49); 7.0691 (4.58); 7.0489 (3.89); 7.038 (3.87); 7.0214(7.92); 6.9888 (0.49); 6.9721 (3.03); 6.9553 (4.72); 6.9362 (2.77);6.9152 (0.92); 6.8984 (7.15); 6.8856 (3.94); 5.9563 (0.33); 5.9291(0.33); 5.8518 (2.45); 5.833 (2.84); 5.824 (2.78); 5.8049 (2.47); 5.7461(10.38); 5.4488 (1.5); 5.4059 (5.41); 5.3629 (5.28); 5.3201 (1.47);4.8695 (2.28); 4.3592 (1.77); 4.325 (1.83); 4.1728 (0.6); 4.156 (5.47);4.1449 (8.21); 4.1328 (5.55); 4.1068 (0.33); 4.0571 (0.4); 4.0392(0.95); 4.0212 (0.98); 4.0037 (0.56); 3.9788 (1.72); 3.9471 (1.77);3.9125 (0.51); 3.8847 (0.51); 3.869 (0.61); 3.8499 (2.63); 3.8422(0.77); 3.8218 (3.05); 3.8071 (3.52); 3.779 (2.93); 3.7293 (0.32);3.6912 (0.34); 3.6615 (0.56); 3.6334 (5.73); 3.6212 (6.37); 3.6112(4.36); 3.5913 (0.63); 3.5808 (0.53); 3.5098 (0.57); 3.4853 (0.69);3.4427 (1.07); 3.4066 (2.9); 3.3781 (4.95); 3.3687 (5.02); 3.3123(2048.24); 3.2908 (15.02); 3.2726 (6.61); 3.233 (53.23); 3.1991 (0.47);3.1883 (0.43); 2.8704 (1.23); 2.8373 (2.06); 2.8084 (1.11); 2.6742 (1);2.6696 (1.27); 2.665 (0.94); 2.5394 (1.88); 2.5093 (73.81); 2.505(136.17); 2.5006 (176.7); 2.4962 (123.71); 2.4919 (60.26); 2.3319(0.88); 2.3273 (1.19); 2.3226 (0.94); 2.1909 (4.67); 2.1267 (1.5);2.0943 (3.12); 2.0691 (2.56); 2.0592 (1.75); 1.9868 (3.35); 1.908 (0.6);1.8417 (0.6); 1.8319 (0.66); 1.8093 (1.34); 1.8028 (1.41); 1.78 (1.28);1.7503 (0.56); 1.6118 (0.66); 1.605 (0.69); 1.5798 (1.35); 1.5731(1.39); 1.5494 (1.28); 1.5429 (1.23); 1.5213 (0.52); 1.5111 (0.54);1.2366 (0.82); 1.1927 (0.99); 1.1749 (1.87); 1.1571 (1); −0.0002 (3.93)Ex. I-20, Solvent: DMSO-d₆ 8.0084 (0.89); 7.9873 (10.75); 7.3268 (0.42);7.313 (1.28); 7.3089 (1.93); 7.3049 (2.44); 7.2901 (6.41); 7.2714(5.75); 7.2543 (0.4); 7.1715 (4.74); 7.1572 (2.24); 7.1135 (0.39);7.0914 (0.41); 7.0734 (2.9); 7.0537 (2.65); 7.0382 (2.36); 7.0212(5.18); 6.9542 (1.78); 6.9355 (3.12); 6.9169 (1.58); 6.898 (4.6); 6.8852(2.5); 5.8386 (1.55); 5.8204 (1.85); 5.8104 (1.72); 5.792 (1.62); 5.7466(1.92); 5.4479 (0.96); 5.4061 (3.68); 5.3796 (2.33); 5.3761 (2.08);5.3639 (4.29); 5.3227 (0.87); 4.5753 (4.18); 4.5595 (3.72); 4.5259(0.51); 4.3602 (1.11); 4.3273 (1.11); 4.0568 (0.71); 4.0392 (2.12);4.0213 (2.17); 4.0036 (0.88); 3.98 (1.02); 3.9458 (1.07); 3.8391 (1.71);3.8104 (1.9); 3.7961 (2.2); 3.7678 (1.82); 3.5678 (0.92); 3.4054 (1.21);3.3968 (1.19); 3.3868 (1.62); 3.3774 (2.32); 3.3675 (1.99); 3.3076(966.41); 3.2843 (14.1); 3.2747 (5.11); 3.2497 (2.72); 3.2315 (2.71);2.8903 (1.83); 2.8675 (0.75); 2.8405 (1.29); 2.8103 (0.68); 2.7313(1.4); 2.6739 (0.63); 2.6693 (0.8); 2.665 (0.62); 2.5392 (1.1); 2.509(47.63); 2.5047 (88.76); 2.5003 (115.69); 2.4959 (80.61); 2.4915(38.79); 2.3314 (0.58); 2.3271 (0.78); 2.3221 (0.57); 2.1247 (0.99);2.1161 (1.57); 2.0939 (1.98); 2.0692 (1.2); 2.0615 (1.12); 1.9868 (9.1);1.8411 (0.43); 1.833 (0.48); 1.8037 (0.88); 1.7812 (1.19); 1.7462(0.85); 1.6883 (16); 1.6711 (13.36); 1.6147 (0.87); 1.5814 (1.04);1.5507 (0.88); 1.5431 (0.83); 1.5216 (0.43); 1.512 (0.39); 1.3983(2.96); 1.3523 (0.58); 1.2986 (0.34); 1.2587 (0.51); 1.2359 (1.43);1.1927 (2.52); 1.175 (5.09); 1.1571 (2.64); 1.1421 (2.46); 1.1205(0.39); 0.0079 (1.11); −0.0002 (24.37); −0.0085 (1.09) Ex. I-21,Solvent: DMSO-d₆ 19.9888 (0.96); 8.7773 (2.8); 8.0193 (16); 7.3512(2.89); 7.3311 (6.43); 7.3106 (4.08); 7.3061 (3.56); 7.1727 (6.69);7.1581 (3.79); 7.0396 (3.35); 7.0221 (8.31); 7.0073 (4.13); 6.9899(9.48); 6.9708 (3.6); 6.9522 (2.67); 6.8982 (7.66); 6.8863 (4.58);5.7254 (2.15); 5.7048 (2.75); 5.6978 (2.67); 5.6775 (2.23); 5.4502(1.34); 5.4072 (5.03); 5.3667 (5.84); 5.325 (1.55); 4.8067 (14.14);4.8007 (14.52); 4.7457 (0.98); 4.3573 (1.76); 4.3279 (1.93); 3.9827(1.72); 3.9459 (1.87); 3.9011 (2.58); 3.8738 (2.92); 3.8579 (3.19);3.8308 (2.68); 3.543 (3.63); 3.5371 (7.54); 3.5309 (3.71); 3.3966 (6.6);3.3763 (7.98); 3.3535 (11.12); 3.3033 (8172.92); 3.0367 (1.37); 2.8727(1.94); 2.8404 (2.75); 2.8131 (2.05); 2.6735 (9.82); 2.6688 (15.1);2.6643 (9.66); 2.6595 (5.58); 2.5389 (17.62); 2.522 (52.17); 2.5087(690.63); 2.5043 (1289.14); 2.4998 (1683.73); 2.4954 (1157.27); 2.491(547.17); 2.3358 (4.09); 2.331 (8.04); 2.3265 (11); 2.322 (7.85); 2.1376(1.7); 2.1029 (3.11); 2.069 (7.23); 1.9865 (1.42); 1.8197 (1.54); 1.7898(1.46); 1.5909 (1.65); 1.5608 (1.44); 1.3984 (1.61); 1.3517 (1.09);1.2979 (1.04); 1.2587 (1.67); 1.236 (5.02); 1.1748 (0.98); 0.8542(0.88); 0.1462 (0.95); 0.0079 (9.36); −0.0002 (181.58); −0.0085 (5.8);−0.1492 (0.7) Ex. I-22, Solvent: DMSO-d₆ 9.9022 (0.44); 8.7772 (0.5);8.6463 (0.42); 8.013 (16); 7.7728 (0.64); 7.7581 (0.33); 7.7407 (0.5);7.5929 (0.52); 7.3484 (9.21); 7.3313 (4.39); 7.3267 (10.28); 7.3088(3.3); 7.2042 (0.38); 7.1754 (7.08); 7.1595 (3.59); 7.0421 (3.74);7.0234 (8.65); 7.0126 (11.26); 7.0076 (4.29); 6.9955 (3.95); 6.9907(9.69); 6.9573 (0.62); 6.9001 (7.6); 6.8876 (4.1); 5.7464 (13.29);5.6954 (2.45); 5.6739 (3.26); 5.6688 (2.96); 5.6472 (2.43); 5.4524(1.52); 5.4104 (5.36); 5.3688 (5.44); 5.3262 (1.43); 4.8008 (14.95);4.7949 (14.86); 4.7407 (0.94); 4.3647 (1.74); 4.3317 (1.8); 4.0571(0.8); 4.0392 (2.27); 4.0214 (2.32); 4.0037 (1.21); 3.985 (1.69); 3.9517(1.8); 3.853 (2.59); 3.826 (2.95); 3.81 (3.38); 3.7831 (2.88); 3.5499(3.63); 3.544 (7.26); 3.5382 (3.57); 3.4766 (0.33); 3.4424 (0.49);3.4165 (1.72); 3.407 (1.58); 3.3895 (5.58); 3.3785 (2.68); 3.3685(4.75); 3.3595 (2.82); 3.3469 (4.7); 3.3252 (7.94); 3.3047 (416.16);3.281 (7.73); 3.2426 (1.41); 3.0372 (0.33); 2.8752 (1.34); 2.8491(2.27); 2.817 (1.23); 2.6737 (0.74); 2.6693 (1.21); 2.6648 (0.7); 2.539(1.68); 2.5087 (48.88); 2.5045 (86.78); 2.5 (110.03); 2.4957 (76.72);2.3313 (0.55); 2.3268 (0.72); 2.3222 (0.49); 2.1375 (1.59); 2.1049(3.18); 2.0691 (2.49); 1.9868 (9.24); 1.908 (0.66); 1.8444 (0.72);1.8229 (1.38); 1.8154 (1.43); 1.792 (1.34); 1.7626 (0.56); 1.6213 (0.6);1.6144 (0.71); 1.5938 (1.36); 1.5841 (1.46); 1.563 (1.36); 1.5542(1.28); 1.534 (0.6); 1.2366 (0.62); 1.1927 (2.59); 1.1749 (5.02); 1.1571(2.49); −0.0002 (5.18) Ex. I-23, Solvent: DMSO-d₆ 10.0348 (11.5); 9.9019(0.99); 8.6468 (0.91); 8.0407 (12.2); 7.9296 (4.81); 7.9028 (1.89);7.8996 (2.76); 7.896 (1.64); 7.884 (2.18); 7.8807 (3.27); 7.8772 (1.89);7.748 (2.07); 7.7287 (3.1); 7.6642 (3); 7.6453 (4.38); 7.6263 (1.82);7.3069 (2.13); 7.1736 (4.82); 7.1587 (2.52); 7.0403 (2.41); 7.0227(5.6); 6.9 (5.04); 6.8868 (2.92); 5.8986 (1.71); 5.8791 (2.02); 5.8715(1.99); 5.8517 (1.78); 5.4502 (0.99); 5.408 (3.84); 5.3905 (0.39);5.3673 (3.62); 5.3257 (0.94); 4.3619 (1.13); 4.3302 (1.22); 4.0571(1.18); 4.0393 (3.62); 4.0215 (3.67); 4.0038 (1.43); 3.9836 (2.98);3.956 (3.14); 3.9405 (3.28); 3.913 (2.22); 3.4478 (2.55); 3.4282 (2.8);3.4158 (1.2); 3.4046 (2.91); 3.3965 (1.55); 3.3854 (3.77); 3.3778(1.74); 3.3681 (1.5); 3.3583 (2.17); 3.3118 (463.38); 3.2415 (1.71);3.1651 (0.35); 2.8729 (0.84); 2.8451 (1.48); 2.8132 (0.86); 2.6744(0.56); 2.6698 (0.75); 2.6651 (0.54); 2.5399 (1.48); 2.5229 (3.26);2.5096 (43.45); 2.5053 (80.56); 2.5008 (105.01); 2.4964 (74.11); 2.4921(36.83); 2.3322 (0.66); 2.3276 (0.82); 2.3231 (0.6); 2.1344 (1.13);2.1019 (2.17); 2.0695 (2.7); 1.987 (16); 1.8408 (0.54); 1.8113 (1);1.7883 (0.92); 1.7607 (0.41); 1.7493 (0.34); 1.6199 (0.42); 1.6115(0.54); 1.5916 (0.94); 1.582 (1.03); 1.5595 (0.93); 1.5512 (0.88);1.5303 (0.4); 1.5208 (0.37); 1.1929 (4.42); 1.1751 (8.81); 1.1573(4.38); −0.0002 (3.62) Ex. I-24, Solvent: DMSO-d₆ 7.9871 (15.6); 7.3167(1.71); 7.3126 (2.43); 7.3058 (3.38); 7.2929 (8.88); 7.2741 (7.96);7.1725 (6.27); 7.1576 (3.14); 7.0391 (3.35); 7.0217 (9.55); 7.0049(4.02); 6.9437 (2.71); 6.9251 (4.79); 6.8992 (6.78); 6.8856 (3.65);5.8162 (2.25); 5.7963 (2.72); 5.7877 (2.66); 5.7676 (2.35); 5.4527(1.31); 5.4103 (4.62); 5.3648 (4.6); 5.3221 (1.31); 4.3603 (1.48);4.3274 (1.53); 4.0577 (1.28); 4.04 (3.76); 4.0222 (3.87); 4.0044 (1.53);3.9836 (1.42); 3.9495 (1.52); 3.8159 (2.63); 3.7978 (6.32); 3.7859(7.44); 3.7735 (4.14); 3.7589 (0.74); 3.7447 (2.63); 3.4189 (0.72);3.4098 (1.27); 3.3928 (4.03); 3.3813 (2.86); 3.3729 (4.36); 3.3622(1.64); 3.3505 (4.06); 3.3424 (2.18); 3.33 (5.88); 3.3135 (263.23);3.2723 (2.56); 3.2422 (1.28); 2.875 (1.04); 2.846 (1.83); 2.8169 (1.04);2.5099 (12.34); 2.5057 (22.74); 2.5012 (29.39); 2.4969 (20.73); 2.4927(10.24); 2.1255 (1.36); 2.0925 (2.77); 2.0697 (1.29); 2.0584 (1.57);1.9873 (16); 1.8358 (0.72); 1.8063 (1.55); 1.7849 (2.84); 1.7543 (2.27);1.7232 (1.96); 1.6931 (1.74); 1.6095 (4.67); 1.5851 (3.35); 1.5554(2.26); 1.5252 (0.62); 1.3974 (9.05); 1.1933 (4.55); 1.1755 (8.83);1.1577 (4.64); 1.1322 (1.11); 1.1016 (2.23); 1.0756 (5.25); 1.0597(4.86); 1.0278 (2.56); 1.0205 (2.72); 0.9908 (1.63); 0.9689 (0.46);0.9607 (0.46); −0.0002 (0.72) Ex. I-25, Solvent: DMSO-d₆ 18.8254 (0.66);18.584 (0.69); 16.784 (0.68); 14.5953 (0.66); 13.1838 (0.64); 12.04(0.63); 8.0258 (0.91); 8.007 (10.22); 7.3381 (1.45); 7.3338 (1.18);7.3145 (5.76); 7.3028 (2.82); 7.2953 (5.13); 7.1697 (4.63); 7.1561(2.21); 7.1342 (2.74); 7.1143 (2.48); 7.0359 (2.08); 7.0204 (4.96);7.0039 (2.08); 6.9865 (2.96); 6.9669 (1.89); 6.8968 (4.55); 6.8846(2.48); 5.8754 (1.85); 5.8574 (1.62); 5.8472 (1.87); 5.8309 (1.76);5.4464 (1.25); 5.4029 (3.77); 5.3627 (3.42); 5.3494 (0.86); 5.3178(1.35); 5.0603 (0.66); 4.8497 (0.85); 4.8244 (7.6); 4.8186 (4.48);4.5358 (0.68); 4.4958 (0.67); 4.4923 (0.77); 4.4719 (0.65); 4.3876(0.7); 4.3572 (1.55); 4.3262 (1.69); 4.2932 (0.75); 4.2478 (0.68);4.1998 (0.66); 4.1293 (0.86); 4.1155 (0.69); 4.0578 (0.98); 4.0393(1.27); 4.0211 (1.5); 3.9724 (1.72); 3.9609 (1.59); 3.9432 (2.01);3.8852 (2.18); 3.8568 (2.79); 3.8418 (2.82); 3.8355 (1.21); 3.8138(2.72); 3.8021 (1.23); 3.7875 (1.24); 3.7714 (1.34); 3.7587 (1.21);3.7525 (1.26); 3.742 (1.25); 3.7382 (1.11); 3.724 (1.34); 3.7016 (1.31);3.6484 (1.54); 3.6357 (1.73); 3.5352 (2.74); 3.4997 (3.05); 3.491(3.38); 3.3112 (8889.96); 3.2453 (6.66); 3.2272 (4.55); 3.1928 (1.43);3.1604 (0.94); 3.1517 (0.71); 3.1382 (0.84); 2.9122 (0.75); 2.8934(0.67); 2.8612 (1.1); 2.8509 (1.04); 2.8326 (1.86); 2.8017 (1.35);2.7871 (0.76); 2.7498 (1.06); 2.7227 (1.1); 2.6948 (2.09); 2.6738(7.06); 2.6694 (8.98); 2.6648 (6.83); 2.643 (1.9); 2.5394 (19.3); 2.5091(540.65); 2.5048 (961.58); 2.5003 (1221.22); 2.496 (846.06); 2.4916(407.46); 2.356 (0.67); 2.3316 (5.95); 2.3271 (8.06); 2.3226 (5.63);2.2293 (1.48); 2.2095 (4.15); 2.2045 (2.56); 2.1911 (3.93); 2.178(1.22); 2.172 (1.42); 2.1328 (1.02); 2.1278 (1.22); 2.0901 (2.25); 2.069(6.74); 2.0555 (1.26); 1.9866 (3.01); 1.8043 (1.08); 1.7803 (0.92);1.5694 (1.02); 1.5662 (0.79); 1.5526 (1.06); 1.3985 (14.05); 1.2973(0.72); 1.259 (1.04); 1.2367 (2.77); 1.1927 (1.09); 1.1749 (2.08);1.1572 (1.15); 1.0542 (8.06); 1.0356 (16); 1.0168 (7.48); 0.9469 (0.73);0.89 (0.75); 0.1461 (0.63); 0.0379 (0.8); 0.008 (6.36); −0.0002(113.74); −0.0085 (4.98); −0.0292 (0.66); −2.0597 (0.67) Ex. I-27,Solvent: DMSO-d₆ 8.4981 (3.72); 8.4875 (3.58); 8.0129 (16); 7.4941(1.02); 7.4744 (3.45); 7.4711 (3.81); 7.4585 (10.06); 7.4554 (9.77);7.4388 (5.13); 7.4208 (6); 7.3851 (3.4); 7.3799 (2.95); 7.3689 (2.71);7.3656 (2.94); 7.3604 (1.95); 7.3508 (1.33); 7.3451 (1.27); 7.3055(2.93); 7.1721 (6.57); 7.1578 (3.56); 7.039 (3.29); 7.0219 (7.47);6.8975 (6.96); 6.886 (3.78); 6.002 (2.73); 5.9834 (3.3); 5.9746 (3.2);5.9557 (2.71); 5.7468 (7.45); 5.4471 (1.31); 5.4042 (5.11); 5.366(5.11); 5.3238 (1.29); 4.3531 (1.67); 4.3222 (1.77); 4.0389 (0.69);4.021 (0.68); 3.9765 (1.68); 3.9408 (4.14); 3.9128 (3.2); 3.8967 (3.34);3.8695 (2.77); 3.7691 (0.34); 3.7614 (0.32); 3.6672 (0.39); 3.6627(0.33); 3.6586 (0.36); 3.6261 (0.34); 3.6154 (0.36); 3.5911 (0.42);3.5384 (0.54); 3.5283 (0.57); 3.5165 (0.61); 3.5024 (0.64); 3.4819(0.77); 3.405 (2.62); 3.3969 (2.62); 3.377 (4.86); 3.3672 (4.57); 3.3061(1839.02); 3.2826 (19.62); 3.257 (5.23); 3.2318 (4.35); 3.213 (3.12);3.1892 (0.36); 2.8688 (1.52); 2.859 (1.85); 2.8485 (3.18); 2.8406(4.71); 2.8307 (3.61); 2.822 (2.42); 2.8122 (2.55); 2.6736 (1.25);2.6693 (1.66); 2.6646 (1.26); 2.6474 (0.36); 2.6296 (0.41); 2.6127(0.49); 2.5391 (2.86); 2.5087 (94.6); 2.5045 (172.38); 2.5001 (221.82);2.4957 (155.71); 2.4914 (76.1); 2.4284 (0.34); 2.4204 (0.33); 2.3269(1.41); 2.3222 (1.02); 2.1264 (1.41); 2.0946 (2.99); 2.0695 (1.74);2.0607 (1.74); 1.9867 (2.17); 1.8377 (0.63); 1.8099 (1.31); 1.7842(1.25); 1.7573 (0.61); 1.6026 (0.73); 1.58 (1.31); 1.5735 (1.33); 1.5506(1.34); 1.5411 (1.24); 1.5203 (0.57); 1.2354 (0.95); 1.1926 (0.65);1.1749 (1.1); 1.1573 (0.61); 0.8903 (0.39); 0.8804 (0.54); 0.7214(1.61); 0.7075 (4.67); 0.7033 (6.63); 0.6913 (5.83); 0.6851 (5.31);0.674 (2.23); 0.6533 (0.45); 0.6338 (0.7); 0.6234 (0.45); 0.5933 (2.69);0.5829 (7.2); 0.5754 (6.42); 0.5664 (4.87); 0.5552 (1.83); 0.0664(0.33); 0.0079 (0.82); −0.0002 (13.42) Ex. I-28, Solvent: DMSO-d₆ 9.9013(0.53); 8.6464 (0.53); 8.0179 (15.28); 7.3196 (2.72); 7.3066 (3.18);7.299 (5.35); 7.2797 (2.76); 7.1734 (6.02); 7.1587 (2.95); 7.0402 (3.1);7.0227 (6.79); 6.9616 (3.89); 6.9443 (8.41); 6.9407 (8.6); 6.919 (3.44);6.913 (2.72); 6.8993 (8.65); 6.8904 (3.05); 6.8869 (3.66); 5.7459(1.42); 5.7185 (2.22); 5.6983 (2.65); 5.6917 (2.59); 5.6714 (2.26);5.4494 (1.23); 5.4075 (4.65); 5.367 (4.47); 5.3239 (1.16); 4.3609(1.49); 4.3283 (1.5); 4.1321 (0.32); 4.105 (5.25); 4.0938 (5.94); 4.0896(5); 4.0819 (5.91); 4.057 (1.44); 4.0392 (3.89); 4.0214 (3.85); 4.0036(1.51); 3.9823 (1.43); 3.9484 (1.53); 3.8922 (2.43); 3.8649 (2.72);3.8492 (3.13); 3.8221 (2.69); 3.6592 (6.77); 3.6515 (5.61); 3.6476(6.96); 3.6443 (5.51); 3.6362 (6); 3.5682 (0.37); 3.4945 (0.54); 3.4891(0.54); 3.4738 (0.81); 3.454 (0.72); 3.421 (1.55); 3.4132 (2.22); 3.3957(5.44); 3.3848 (4.28); 3.3756 (6.39); 3.3529 (8.44); 3.3143 (1657.1);3.2997 (69.45); 3.2708 (3.69); 3.2406 (1.59); 3.1928 (0.32); 3.1214(0.34); 2.872 (0.94); 2.844 (1.7); 2.8143 (1); 2.6743 (0.71); 2.6698(0.93); 2.6653 (0.73); 2.5657 (1.67); 2.5395 (1.44); 2.5095 (56.57);2.5052 (103.94); 2.5007 (134.27); 2.4964 (93.13); 2.492 (44.99); 2.4479(0.38); 2.3322 (0.71); 2.3276 (0.85); 2.3227 (0.68); 2.1347 (1.33);2.1026 (2.58); 2.069 (2.13); 1.9868 (16); 1.9081 (0.57); 1.8414 (0.58);1.8114 (1.2); 1.7888 (1.09); 1.7601 (0.49); 1.6225 (0.56); 1.6109(0.66); 1.5902 (1.12); 1.5809 (1.22); 1.5612 (1.08); 1.552 (1.02); 1.53(0.49); 1.5202 (0.42); 1.3983 (0.86); 1.2375 (0.41); 1.1928 (4.44);1.175 (8.82); 1.1572 (4.31); −0.0002 (1.96) Ex. I-29, Solvent: DMSO-d₆7.9726 (11.82); 7.4193 (1.12); 7.3983 (2.39); 7.3812 (2.34); 7.3608(1.18); 7.3089 (2.02); 7.1757 (4.66); 7.1592 (2.23); 7.0424 (2.27);7.0231 (5.17); 6.9821 (3.52); 6.961 (3.13); 6.8999 (4.73); 6.8875(3.85); 6.8642 (2.22); 6.8429 (1.67); 6.0641 (1.51); 6.0423 (1.98);6.0345 (1.89); 6.0117 (1.64); 5.4562 (0.97); 5.413 (3.42); 5.3697(3.39); 5.3271 (1); 4.8073 (0.37); 4.7737 (5.62); 4.768 (5.6); 4.3713(1.13); 4.3692 (1.17); 4.3406 (1.14); 3.9911 (1.17); 3.9584 (1.19);3.7947 (1.21); 3.7659 (1.47); 3.7544 (1.85); 3.7222 (1.59); 3.6983(0.36); 3.6678 (0.43); 3.6525 (0.39); 3.5964 (0.45); 3.5693 (0.5);3.5395 (2.27); 3.5178 (2.32); 3.4968 (1.94); 3.4754 (2.07); 3.4274(2.13); 3.398 (3.64); 3.3882 (3.45); 3.3797 (3.8); 3.3127 (2744.28);3.2894 (25.2); 3.257 (2.1); 2.8782 (0.78); 2.8521 (1.41); 2.8219 (0.8);2.6739 (1.19); 2.6696 (1.62); 2.665 (1.2); 2.6259 (0.33); 2.6072 (0.34);2.5855 (0.5); 2.5395 (2.35); 2.5093 (97.19); 2.505 (179.71); 2.5006(232.83); 2.4962 (162.42); 2.4919 (78.86); 2.332 (1.16); 2.3271 (1.52);2.3222 (1.05); 2.1515 (0.98); 2.1201 (1.96); 2.0786 (1.21); 2.0689(6.74); 1.8494 (0.51); 1.8217 (0.93); 1.7992 (0.89); 1.759 (8.2); 1.7533(16); 1.7477 (7.73); 1.6309 (0.41); 1.6235 (0.49); 1.5999 (0.95); 1.592(0.98); 1.5718 (0.86); 1.5395 (0.39); 1.3983 (0.42); 1.2369 (0.61);−0.0002 (14.45) Ex. I-30, Solvent: DMSO-d₆ 7.9681 (16); 7.433 (1.5);7.416 (1.98); 7.4119 (3.1); 7.3952 (3.13); 7.391 (1.89); 7.3739 (1.51);7.3085 (2.56); 7.175 (5.8); 7.1585 (2.74); 7.0418 (2.83); 7.0226 (6.92);7.0121 (4.36); 6.9908 (3.84); 6.9093 (3.01); 6.9008 (5.87); 6.8865(5.33); 6.8644 (1.87); 6.074 (1.94); 6.0516 (2.36); 6.0436 (2.19);6.0213 (1.96); 5.4545 (1.14); 5.411 (4.19); 5.369 (4.16); 5.3271 (1.09);4.887 (0.53); 4.8816 (0.59); 4.8472 (6.66); 4.8417 (10.99); 4.8361(6.08); 4.802 (0.48); 4.7962 (0.58); 4.3673 (1.31); 4.3338 (1.42);3.9904 (1.39); 3.9536 (1.47); 3.8311 (0.43); 3.8095 (1.58); 3.7769(1.77); 3.7681 (2.13); 3.7375 (1.93); 3.5278 (3.35); 3.5207 (4.59);3.5148 (8.43); 3.5088 (5); 3.4848 (3.01); 3.4631 (3.39); 3.3942 (7.5);3.3307 (5101.71); 3.3077 (39.28); 3.2505 (2.33); 3.214 (0.93); 3.1513(0.33); 2.8803 (0.83); 2.8505 (1.57); 2.8219 (0.84); 2.6753 (1.19);2.6708 (1.61); 2.6661 (1.17); 2.6613 (0.59); 2.5407 (2.04); 2.5107(94.07); 2.5063 (176.46); 2.5017 (231.85); 2.4973 (160.85); 2.4929(77.91); 2.3331 (1.24); 2.3283 (1.57); 2.1548 (1.15); 2.11.71 (2.28);2.0796 (1.44); 2.0684 (11.58); 1.8497 (0.53); 1.8211 (1.07); 1.7995(1.06); 1.6243 (0.49); 1.5944 (1.06); 1.5722 (1.05); 1.5414 (0.42);1.2375 (0.37); −0.0002 (12.57) Ex. I-31, Solvent: DMSO-d₆ 10.2929 (9.8);8.7763 (4.66); 8.2983 (15.34); 8.0298 (3.08); 8.0268 (3.07); 8.0104(3.61); 8.0074 (3.55); 7.9472 (2.56); 7.9445 (2.64); 7.9278 (4.4); 7.925(4.28); 7.8912 (2.38); 7.8878 (2.33); 7.8727 (3.9); 7.8692 (3.55);7.8536 (1.98); 7.8502 (1.68); 7.7879 (2.19); 7.7685 (3.22); 7.7506(1.42); 7.4325 (16); 7.3636 (0.36); 7.3559 (0.57); 7.3182 (2.51); 7.3032(1.2); 7.284 (0.51); 7.1849 (5.51); 7.1696 (3.14); 7.1643 (3.27); 7.157(1.77); 7.1516 (1.2); 7.1117 (0.6); 7.0519 (2.69); 7.0363 (1.62); 7.0284(6.38); 7.021 (3.52); 6.9056 (6.47); 6.8924 (4); 6.8853 (1.94); 5.7459(7.44); 5.4676 (1.16); 5.4256 (4.12); 5.3959 (2.55); 5.3844 (4.4);5.3658 (1.99); 5.3538 (2.02); 5.3425 (1.57); 5.3066 (1.18); 5.1928(0.67); 4.5401 (0.32); 4.486 (0.36); 4.3976 (1.37); 4.3587 (1.65);4.3162 (0.88); 4.2906 (0.34); 4.2601 (0.36); 4.2062 (0.33); 4.1853(0.33); 4.1801 (0.4); 4.149 (0.45); 4.1315 (1.07); 4.114 (0.98); 4.0994(0.42); 4.0962 (0.51); 4.0567 (0.9); 4.0391 (2.37); 4.0214 (3.01);4.0035 (1.62); 3.9809 (1.98); 3.9407 (0.89); 3.8995 (0.43); 3.8305(0.46); 3.8229 (0.47); 3.8148 (0.51); 3.8009 (0.56); 3.7917 (0.49);3.7729 (0.5); 3.739 (0.58); 3.7245 (0.59); 3.7066 (0.58); 3.6805 (0.67);3.6669 (0.75); 3.6348 (0.77); 3.5909 (0.8); 3.5762 (0.89); 3.544 (1.01);3.5038 (1.37); 3.4839 (2.13); 3.456 (3.53); 3.4474 (3.04); 3.4271(3.51); 3.4141 (3.55); 3.3145 (4026.52); 3.2023 (0.7); 3.1638 (0.36);3.037 (2.37); 2.9084 (0.93); 2.8737 (1.7); 2.8499 (3.05); 2.8096 (0.56);2.6992 (0.37); 2.6746 (1.93); 2.6698 (2.51); 2.6651 (1.88); 2.6417(0.45); 2.6177 (0.56); 2.6052 (0.65); 2.5399 (3.63); 2.5096 (137.51);2.5053 (254.27); 2.5008 (329.93); 2.4964 (227.27); 2.492 (107.64); 2.332(1.47); 2.3275 (2.04); 2.3231 (1.54); 2.1956 (1.21); 2.1611 (2.32);2.1257 (1.67); 2.102 (1.16); 2.0848 (14.59); 2.0692 (1.6); 2.0476 (0.5);2.0429 (0.41); 2.0149 (0.32); 1.9868 (8.85); 1.8984 (0.58); 1.8707(1.17); 1.8491 (1.21); 1.8178 (0.85); 1.7906 (0.67); 1.7861 (0.59);1.7788 (0.61); 1.7388 (0.38); 1.6831 (0.78); 1.651 (1.48); 1.6215(1.46); 1.589 (0.85); 1.5803 (0.66); 1.5602 (0.51); 1.5561 (0.55);1.5531 (0.5); 1.5286 (0.47); 1.525 (0.44); 1.3986 (1.68); 1.2402 (1.4);1.2221 (2.07); 1.2043 (0.95); 1.1928 (2.53); 1.175 (4.9); 1.1572 (2.49);1.1471 (0.43); 0.9453 (0.33); −0.0002 (13.04); −0.0086 (0.54) Ex. I-32,Solvent: DMSO-d₆ 8.0564 (0.67); 8.0421 (16); 7.4458 (3.11); 7.442(3.43); 7.4268 (3.82); 7.4227 (4.75); 7.4155 (1.9); 7.4005 (3.86);7.3961 (3.09); 7.3811 (2.97); 7.3767 (2.33); 7.3042 (5.74); 7.2881(4.13); 7.2853 (4.14); 7.2692 (1.72); 7.2665 (1.62); 7.202 (0.34); 7.171(6.68); 7.1569 (3.32); 7.1431 (4.64); 7.1406 (4.46); 7.1231 (4.07);7.1206 (3.69); 7.0377 (3.28); 7.0209 (7.38); 6.8985 (6.33); 6.885(3.66); 5.7504 (2.42); 5.7304 (2.9); 5.7216 (2.69); 5.7019 (2.48);5.4518 (1.33); 5.4089 (4.58); 5.3638 (4.56); 5.3213 (1.3); 4.3853(0.42); 4.3618 (1.57); 4.3593 (1.58); 4.3289 (1.54); 4.0569 (0.94);4.0391 (2.62); 4.0214 (2.58); 4.0034 (1.17); 3.9821 (1.51); 3.9509(1.7); 3.8783. (2.45); 3.8498 (2.86); 3.8355 (3.33); 3.8219 (0.49);3.8068 (2.77); 3.7302 (0.35); 3.7053 (0.35); 3.6846 (0.39); 3.633(0.44); 3.6077 (0.5); 3.58 (0.49); 3.5626 (0.57); 3.4258 (2.02); 3.4165(2.62); 3.3882 (4.64); 3.3779 (4.5); 3.3103 (1658.59); 3.262 (5.58);3.2419 (4.22); 3.0574 (14.26); 2.8746 (0.98); 2.8433 (1.78); 2.8131(0.98); 2.6738 (1.19); 2.6694 (1.65); 2.6647 (1.19); 2.6604 (0.69);2.5863 (1.14); 2.5775 (1.86); 2.5687 (1.53); 2.5587 (2.41); 2.5497(3.93); 2.5397 (3.62); 2.5092 (90.95); 2.5048 (169.36); 2.5003 (221.44);2.4959 (153.89); 2.4915 (73.81); 2.3316 (1.05); 2.3268 (1.46); 2.3226(1.08); 2.1566 (0.5); 2.1534 (0.47); 2.1288 (1.46); 2.0952 (2.79); 2.069(4.5); 2.0094 (1.48); 1.9867 (12.07); 1.937 (1.48); 1.9072 (1.58);1.8514 (0.38); 1.8366 (0.59); 1.8075 (1.63); 1.7742 (1.62); 1.691(2.87); 1.6777 (2.37); 1.6661 (2.03); 1.6382 (1.11); 1.6104 (2.08);1.6039 (2.28); 1.583 (2.59); 1.553 (1.62); 1.5441 (1.47); 1.5219 (0.68);1.5096 (1.04); 1.5009 (1.3); 1.4939 (1); 1.4719 (2.77); 1.4428 (2.64);1.422 (1.04); 1.4121 (1.32); 1.3984 (4.82); 1.3599 (0.49); 1.3522 (0.4);1.3237 (0.97); 1.3161 (0.74); 1.2936 (1.53); 1.2855 (1.57); 1.2775(1.47); 1.2539 (2.13); 1.221 (3.2); 1.1927 (6.06); 1.1749 (7.28); 1.1571(3.48); 1.1511 (0.66); 1.0561 (0.62); 0.8896 (0.33); 0.008 (1.07);−0.0002 (23.89); −0.0084 (1.03) Ex. I-33, Solvent: DMSO-d₆ 8.0449(0.85); 8.0307 (16); 7.4467 (3.19); 7.4426 (3.33); 7.4274 (3.8); .7.4236(4.09); 7.4145 (1.89); 7.4098 (1.62); 7.3954 (3.73); 7.3906 (2.89);7.3757 (2.96); 7.3713 (2.2); 7.3109 (3.24); 7.3078 (3.83); 7.2921(3.92); 7.2892 (3.94); 7.2733 (1.65); 7.2338 (0.34); 7.1715 (10.39);7.1572 (3.81); 7.1538 (4.36); 7.1511 (3.68); 7.0383 (3.11); 7.0214(7.15); 6.8995 (6.18); 6.8855 (3.42); 5.7594 (2.31); 5.74 (2.86); 5.7311(2.73); 5.7112 (2.3); 5.4498 (1.37); 5.4085 (4.59); 5.3638 (4.67);5.3202 (1.27); 4.7805 (0.32); 4.7391 (0.32); 4.3623 (1.62); 4.3289(1.63); 4.26 (0.32); 4.2317 (0.37); 4.2084 (0.37); 4.192 (0.35); 4.186(0.41); 4.1654 (0.39); 4.1349 (0.4); 4.1203 (0.4); 4.0568 (1.39); 4.0392(3.53); 4.0213 (3.67); 4.0034 (1.64); 3.9822 (1.64); 3.9482 (1.7);3.8942 (2.81); 3.8653 (3.21); 3.8509 (3.36); 3.8224 (2.98); 3.7494(0.57); 3.6821 (0.69); 3.6683 (0.77); 3.6417 (0.8); 3.6015 (1.59);3.5876 (1.16); 3.5664 (1.08); 3.5378 (1.18); 3.5131 (1.33); 3.4823(1.59); 3.4764 (1.78); 3.3833 (8.42); 3.3191 (4565.63); 3.2922 (16.26);3.272 (8.14); 3.2484 (4.61); 3.2289 (3.64); 3.1704 (0.37); 3.0574(3.22); 2.8707 (1.03); 2.8433 (1.69); 2.8113 (1.01); 2.6746 (1.55);2.6701 (2.23); 2.6655 (1.58); 2.6609 (0.87); 2.54 (3.1); 2.5098(135.46); 2.5054 (250.35); 2.501 (325.5); 2.4965 (224.28); 2.4921(106.69); 2.3322 (1.5); 2.3275 (2.16); 2.3234 (1.54); 2.1319 (1.58);2.0953 (2.73); 2.0687 (6.45); 1.9868 (14.8); 1.9083 (0.38); 1.8733(0.76); 1.8565 (1.63); 1.8414 (2.92); 1.8356 (1.89); 1.8307 (2.09);1.823 (1.8); 1.8106 (1.92); 1.7703 (1.41); 1.7605 (1.37); 1.7529 (0.81);1.7439 (0.83); 1.601 (0.65); 1.5799 (1.23); 1.5733 (1.29); 1.5522(1.15); 1.5199 (0.57); 1.3984 (5.98); 1.3499 (0.37); 1.2364 (1.21);1.1928 (4.43); 1.175 (8.37); 1.1572 (4.29); 1.1241 (0.46); 1.107 (0.42);1.0735 (1.13); 1.0654 (1.2); 1.0527 (2.77); 1.0472 (3.27); 1.0319(5.75); 1.021 (4.22); 1.0149 (4.83); 1.0087 (4.54); 1.0042 (2.9); 0.998(2.4); 0.9888 (2.88); 0.9834 (2.07); 0.9757 (2.28); 0.964 (2.97); 0.95(1.67); 0.9445 (1.47); 0.9312 (0.76); 0.8904 (0.66); 0.8346 (0.33);0.7914 (0.38); 0.7855 (0.37); 0.768 (0.32); 0.008 (1.2); −0.0002(26.72); −0.0085 (1.09) Ex. I-34, Solvent: DMSO-d₆ 8.7767 (1.01); 8.0195(10.27); 7.3364 (2.01); 7.3283 (0.48); 7.3162 (4.18); 7.306 (2.23);7.2959 (2.57); 7.1727 (4.18); 7.1582 (2.25); 7.0395 (2.09); 7.0222(4.95); 6.9869 (3.67); 6.9805 (3.48); 6.9752 (3.68); 6.9439 (1.88);6.9421 (1.89); 6.9378 (1.57); 6.9234 (1.72); 6.9214 (1.68); 6.9173(1.56); 6.9152 (1.42); 6.8992 (4.59); 6.8863 (2.54); 5.7461 (6.78);5.7267 (1.38); 5.7067 (1.64); 5.6996 (1.6); 5.6795 (1.4); 5.4492 (0.78);5.4067 (3.05); 5.3663 (3.24); 5.3236 (0.83); 4.7544 (4.46); 4.7491(8.07); 4.7438 (4.45); 4.3597 (0.92); 4.3273 (1); 3.9814 (0.9); 3.9469(0.99); 3.9041 (1.5); 3.8767 (1.71); 3.861 (1.94); 3.8337 (1.62); 3.4219(0.62); 3.4121 (0.92); 3.4018 (0.85); 3.3904 (2.75); 3.3835 (1.97);3.3702 (2.79); 3.3542 (2.09); 3.3471 (3.57); 3.3113 (921.47); 3.2763(3.03); 3.2402 (1.32); 2.8904 (0.52); 2.8715 (0.76); 2.8421 (1.27);2.8138 (0.71); 2.7311 (0.35); 2.6741 (0.56); 2.6696 (0.75); 2.665(0.56); 2.6541 (0.51); 2.5697 (0.39); 2.5396 (0.86); 2.5227 (2.51);2.5094 (40.17); 2.505 (76.36); 2.5005 (101.04); 2.4961 (70.54); 2.4917(34.3); 2.3362 (0.35); 2.3319 (0.57); 2.3273 (0.77); 2.3226 (0.56); 2.22(0.79); 2.2148 (1.38); 2.2094 (0.92); 2.2013 (1.96); 2.196 (3.73);2.1907 (2.01); 2.1825 (2.06); 2.1773 (3.84); 2.172 (1.98); 2.164 (0.93);2.1586 (1.52); 2.1533 (0.96); 2.1354 (1.27); 2.0999 (1.92); 2.069(1.62); 1.9868 (1); 1.8389 (0.44); 1.8096 (0.86); 1.7859 (0.8); 1.7782(0.76); 1.7567 (0.38); 1.6199 (0.38); 1.6092 (0.46); 1.588 (0.8); 1.5795(0.88); 1.5576 (0.82); 1.5498 (0.8); 1.5292 (0.39); 1.439 (0.7); 1.4171(0.63); 1.3982 (9.94); 1.3845 (0.84); 1.3525 (0.44); 1.2989 (0.35);1.2588 (0.52); 1.2359 (0.97); 1.1928 (0.36); 1.175 (0.61); 1.1572(0.34); 1.0618 (0.37); 1.0419 (7.86); 1.0232 (16); 1.0045 (7.35); 0.9857(0.4); −0.0002 (5.44) Ex. I-35, Solvent: DMSO-d₆ 8.0082 (11.59); 7.3952(0.36); 7.3372 (1.11); 7.3331 (1.49); 7.3138 (6.53); 7.3043 (2.48);7.2949 (6.01); 7.2628 (0.73); 7.2251 (0.37); 7.1709 (4.28); 7.157(2.11); 7.1289 (3.52); 7.1089 (2.94); 7.09 (0.84); 7.0377 (2.14); 7.021(4.87); 7.0024 (1.97); 6.985 (3.29); 6.9666 (1.54); 6.9549 (0.45);6.8983 (4.09); 6.8851 (2.38); 5.9134 (0.58); 5.9074 (0.64); 5.8763(1.66); 5.8583 (2.03); 5.8485 (2.25); 5.8304 (1.74); 5.7452 (3.89);5.4469 (0.79); 5.4047 (3.02); 5.3634 (2.99); 5.321 (0.78); 4.8129 (6.5);4.807 (6.58); 4.3596 (0.94); 4.3268 (0.95); 3.9783 (0.88); 3.9439(0.93); 3.8847 (1.63); 3.8568 (1.89); 3.8418 (2.12); 3.814 (1.78);3.4127 (0.72); 3.4036 (1.12); 3.3947 (1.14); 3.3846 (1.56); 3.3752(2.37); 3.3656 (2.18); 3.3185 (1355.83); 3.2952 (14.91); 3.2803 (4.54);3.2621 (4.23); 3.2372 (2.87); 3.2192 (2.45); 2.8632 (0.68); 2.8339(1.16); 2.8055 (0.69); 2.6793 (0.39); 2.6747 (0.72); 2.6701 (0.98);2.6657 (0.73); 2.6608 (0.38); 2.5401 (1.07); 2.5233 (3.57); 2.5099(54.86); 2.5055 (103.8); 2.501 (136.66); 2.4966 (94.58); 2.4922 (45.14);2.3369 (0.42); 2.3324 (0.74); 2.3277 (0.99); 2.3232 (0.73); 2.3185(0.39); 2.1279 (0.99); 2.094 (1.88); 2.0688 (2.48); 2.0602 (1.07);1.9869 (0.33); 1.8234 (7.69); 1.8177 (16); 1.812 (8.61); 1.7817 (0.84);1.7746 (0.79); 1.7526 (0.37); 1.6799 (0.38); 1.6512 (0.33); 1.6118(0.38); 1.6008 (0.41); 1.5806 (0.76); 1.5708 (0.8); 1.5502 (0.75); 1.541(0.71); 1.5201 (0.34); 1.3524 (0.58); 1.2985 (0.97); 1.259 (1.38);1.2362 (1.58); 0.0079 (0.45); −0.0002 (10.51); −0.0085 (0.43) Ex. I-36,Solvent: DMSO-d₆ 8.0517 (0.55); 8.0421 (9.39); 7.487 (1.77); 7.483(2.13); 7.468 (2.33); 7.4639 (2.89); 7.4565 (1.15); 7.4416 (2.4); 7.437(1.9); 7.422 (1.97); 7.4176 (1.52); 7.3704 (1.79); 7.3678 (1.9); 7.3517(2.43); 7.3489 (2.47); 7.3327 (1.03); 7.3302 (0.94); 7.3034 (1.8);7.2377 (2.9); 7.2349 (2.76); 7.2177 (2.46); 7.215 (2.29); 7.17 (4.06);7.157 (2.01); 7.0368 (2.04); 7.021 (4.53); 6.8989 (4.2); 6.8851 (2.3);5.8325 (1.5); 5.8127 (1.73); 5.8042 (1.7); 5.7843 (1.5); 5.4469 (0.77);5.4051 (3.05); 5.3656 (3); 5.3234 (0.79); 4.3588 (0.94); 4.3279 (1);4.0806 (1.41); 4.0539 (4.47); 4.0391 (4.17); 4.0269 (4.73); 4.0214(4.41); 4.0033 (1.92); 4.0002 (1.89); 3.9825 (0.99); 3.9466 (1.04);3.9162 (1.61); 3.8879 (1.82); 3.873 (1.94); 3.8448 (1.68); 3.4712(0.35); 3.413 (1.18); 3.4024 (1.14); 3.3936 (1.6); 3.3845 (2.21); 3.3755(1.94); 3.355 (2.63); 3.3075 (760.65); 3.261 (3.18); 3.2408 (2.56);3.2176 (1.78); 3.1978 (1.63); 2.8708 (0.64); 2.8411 (1.16); 2.8112(0.64); 2.6738 (0.6); 2.6691 (0.78); 2.6648 (0.58); 2.5392 (1.14); 2.509(44.2); 2.5047 (81.04); 2.5003 (104.48); 2.4959 (71.67); 2.4915 (33.77);2.3317 (0.47); 2.3269 (0.69); 2.3225 (0.49); 2.1308 (0.83); 2.0988(1.7); 2.0691 (1.76); 1.9867 (16); 1.84 (0.33); 1.8353 (0.35); 1.8234(0.38); 1.8038 (0.77); 1.7819 (0.73); 1.6165 (0.51); 1.5845 (0.78);1.5529 (0.73); 1.5438 (0.7); 1.5234 (0.35); 1.3983 (4.85); 1.2592(0.37); 1.236 (0.78); 1.1927 (4.49); 1.1749 (8.81); 1.1571 (4.35);0.0079 (1.6); −0.0002 (33.58); −0.0085 (1.31) Ex. I-37, Solvent: DMSO-d₆9.286 (0.77); 8.0342 (0.41); 8.0227 (6.59); 7.4384 (1.2); 7.4218 (1.56);7.4179 (1.38); 7.4022 (0.48); 7.3983 (0.44); 7.378 (1.63); 7.3675(2.98); 7.3618 (4.85); 7.359 (4.72); 7.3489 (1.31); 7.3418 (1.25);7.3362 (1); 7.326 (0.42); 7.3199 (0.42); 7.3059 (1.22); 7.1727 (2.75);7.1577 (1.34); 7.0393 (1.33); 7.0217 (3.07); 6.8983 (2.75); 6.8858(1.55); 6.1213 (1); 6.1009 (1.24); 6.0939 (1.18); 6.0731 (1.03); 5.7462(4.79); 5.4499 (0.57); 5.4078 (2.02); 5.3661 (2.03); 5.3244 (0.54);4.3621 (0.65); 4.3289 (0.68); 4.057 (0.43); 4.0391 (1.24); 4.0214(1.28); 4.0035 (0.54); 3.98 (0.7); 3.9542 (1.5); 3.9265 (1.25); 3.9104(1.33); 3.8829 (1.06); 3.4406 (0.38); 3.4149 (0.94); 3.4044 (0.87);3.3859 (1.6); 3.3769 (1.44); 3.3562 (2.16); 3.3105 (820.01); 3.2875(8.8); 3.2661 (2.52); 3.2457 (1.52); 3.2383 (0.81); 3.0528 (0.75);3.0357 (16); 2.8685 (0.47); 2.8395 (0.8); 2.8139 (0.48); 2.6741 (0.63);2.6694 (0.85); 2.6651 (0.6); 2.5396 (1.07); 2.5225 (3.59); 2.5092(46.39); 2.5049 (85.81); 2.5004 (111.31); 2.4961 (77.41); 2.4918(37.22); 2.3316 (0.51); 2.3272 (0.72); 2.3226 (0.53); 2.1304 (0.57);2.101 (1.15); 2.069 (1.34); 1.9867 (5.13); 1.8115 (0.51); 1.7875 (0.47);1.5885 (0.52); 1.5789 (0.52); 1.5569 (0.5); 1.549 (0.47); 1.1927 (1.42);1.1749 (2.77); 1.1571 (1.36); −0.0002 (3.8) Ex. I-38, Solvent: DMSO-d₆8.045 (16); 7.7484 (0.42); 7.5602 (3.52); 7.5418 (4.61); 7.478 (0.38);7.4714 (0.79); 7.4685 (0.79); 7.4518 (3.13); 7.4487 (3.22); 7.4363 (8);7.4329 (10.02); 7.4188 (1.4); 7.3968 (0.35); 7.3804 (2.83); 7.3742(2.42); 73615 (2.72); 7.3587 (2.27); 7.355 (2.18); 7.346 (1.48); 7.3395(1.46); 7.3056 (2.68); 7.1723 (6.13); 7.158 (3.08); 7.039 (3.04); 7.0219(7.05); 6.9004 (6.15); 6.8861 (3.37); 6.0236 (2.56); 6.0054 (3); 5.9958(2.9); 5.9775 (2.56); 5.7443 (11.99); 5.4496 (1.18); 5.4071 (4.43);5.3648 (4.59); 5.3223 (1.19); 4.542 (13.91); 4.522 (0.34); 4.3622(1.38); 4.3285 (1.5); 4.0575 (0.54); 4.0398 (1.48); 4.0219 (1.67);4.0127 (2.68); 4.0042 (0.87); 3.9848 (4); 3.9696 (4.08); 3.9418 (3.99);3.8728 (0.33); 3.5684 (1.48); 3.4573 (0.73); 3.4092 (2.36); 3.3992(2.48); 3.3798 (5.27); 3.3333 (1502.56); 3.3141 (12.84); 3.3103 (13.57);3.2958 (5.87); 3.2647 (2.23); 3.2351 (1.18); 2.8911 (0.39); 2.8659(0.95); 2.8361 (1.67); 2.8077 (0.91); 2.676 (0.65); 2.6715 (0.81); 2.667(0.59); 2.5415 (1.24); 2.5246 (3.49); 2.5113 (47.16); 2.507 (88.52);2.5025 (115.82); 2.4981 (80.76); 2.4937 (38.83); 2.3339 (0.6); 2.3291(0.78); 2.3245 (0.57); 2.1301 (1.22); 2.0971 (2.53); 2.0688 (1.68);2.0381 (0.44); 1.9873 (6.06); 1.8376 (0.53); 1.817 (1.07); 1.8084(1.14); 1.7853 (1.06); 1.7774 (1.02); 1.7566 (0.44); 1.6124 (0.49);1.6027 (0.57); 1.5815 (1.08); 1.573 (1.18); 1.5512 (1.13); 1.5423(1.05); 1.522 (0.49); 1.2365 (3.92); 1.1933 (1.69); 1.1755 (3.37);1.1657 (1.98); 1.1577 (1.87); 0.8542 (0.44); −0.0002 (3.1) Ex. I-39,Solvent: DMSO-d₆ 8.7771 (2.11); 8.0267 (0.4); 8.0235 (0.36); 8.006 (16);7.9817 (1.67); 7.5997 (0.93); 7.3469 (1.88); 7.3426 (2.19); 7.3238(9.44); 7.3048 (11.46); 7.171 (7.57); 7.1571 (4.87); 7.1515 (4.97);7.1318 (3.93); 7.0377 (3.99); 7.0213 (11.21); 7.0032 (4.63); 6.9848(2.64); 6.9642 (0.53); 6.8979 (7.65); 6.8855 (4.6); 5.8875 (2.21);5.8695 (2.62); 5.8598 (2.63); 5.8418 (2.35); 5.7464 (6.68); 5.4479(1.38); 5.4053 (5.11); 5.3641 (5.49); 5.3214 (1.43); 4.8769 (12.77);4.871 (12.92); 4.7991 (1.38); 4.3569 (1.65); 4.3255 (1.77); 4.1206(0.91); 4.1143 (0.93); 4.039 (0.77); 4.0213 (0.89); 4.0032 (0.45);3.9751 (1.7); 3.946 (1.94); 3.919 (0.49); 3.8967 (2.45); 3.8688 (2.85);3.8537 (3.11); 3.8259 (2.56); 3.5666 (3.33); 3.5607 (7.23); 3.5548(3.28); 3.4323 (0.43); 3.4124 (1.05); 3.4032 (1.62); 3.3932 (1.55);3.3835 (2.24); 3.3747 (3.41); 3.365 (3.02); 3.3084 (1959.21); 3.2859(20.62); 3.2716 (9.69); 3.2536 (7.04); 3.2286 (5.39); 3.2105 (4.11);3.155 (0.95); 3.1487 (1.16); 3.1424 (0.94); 3.1116 (0.56); 3.0552(0.43); 3.0369 (0.75); 2.9398 (0.48); 2.9243 (0.36); 2.9089 (0.36);2.8899 (0.59); 2.8646 (1.51); 2.8491 (1.15); 2.8376 (2.33); 2.8047(1.39); 2.7322 (0.36); 2.695 (0.48); 2.6737 (1.99); 2.6692 (5.8); 2.5654(0.83); 2.5394 (4.15); 2.5224 (9.75); 2.5091 (122.25); 2.5047 (229.43);2.5002 (302.8); 2.4958 (216.89); 2.4914 (108.87); 2.4039 (0.74); 2.3316(1.84); 2.327 (2.36); 2.3225 (1.8); 2.2882 (0.41); 2.2805 (0.44); 2.2698(0.37); 2.2532 (0.4); 2.2371 (0.36); 2.2001 (0.39); 2.1792 (0.43);2.1286 (1.81); 2.0942 (3.42); 2.0691 (3.06); 2.0221 (0.37); 2.0091(0.41); 1.9867 (3.55); 1.9078 (0.34); 1.8345 (0.85); 1.8054 (1.56);1.7828 (1.53); 1.7525 (0.72); 1.6103 (0.74); 1.5994 (0.81); 1.5803(1.56); 1.5702 (1.54); 1.5491 (1.56); 1.5415 (1.36); 1.5207 (0.71);1.4701 (1.14); 1.4062 (2.26); 1.3982 (0.81); 1.3522 (0.8); 1.337 (0.35);1.2983 (1.38); 1.2844 (0.38); 1.259 (2.18); 1.2363 (3.16); 1.1927(1.18); 1.1749 (2.11); 1.1571 (1.17); 0.8706 (0.35); 0.8542 (0.53);0.8374 (0.36); 0.0079 (1.18); −0.0002 (23.73); −0.0084 (1.06) Ex. I-40,Solvent: DMSO-d₆ 9.7795 (2.15); 8.0164 (4.15); 7.3719 (1.96); 7.3505(2.62); 7.3073 (0.7); 7.2321 (2.84); 7.2106 (2.14); 7.1739 (1.6); 7.159(0.81); 7.0407 (0.8); 7.023 (1.82); 6.8997 (1.61); 6.8871 (0.92); 5.7081(0.57); 5.687 (0.73); 5.6815 (0.7); 5.6602 (0.59); 5.4515 (0.34); 5.4089(1.22); 5.3673 (1.2); 4.3633 (0.38); 4.3298 (0.4); 4.0569 (1.23); 4.0391(3.66); 4.0213 (3.7); 4.0035 (1.32); 3.9825 (0.39); 3.9505 (0.41);3.8743 (0.6); 3.8471 (0.69); 3.8313 (0.79); 3.8043 (0.67); 3.5676(0.45); 3.4145 (0.47); 3.387 (1.51); 3.3765 (0.78); 3.3661 (1.4); 3.3576(1.06); 3.344 (1.94); 3.3089 (349.24); 3.242 (0.49); 2.9856 (11.18);2.8443 (0.49); 2.674 (0.35); 2.6693 (0.43); 2.6647 (0.34); 2.5393(0.77); 2.5223 (2.25); 2.509 (25.66); 2.5047 (46.92); 2.5003 (60.77);2.4959 (42.78); 2.4915 (20.9); 2.3316 (0.33); 2.327 (0.43); 2.1462(0.33); 2.1378 (0.36); 2.1018 (0.72); 2.0692 (0.49); 1.9867 (16); 1.8234(0.32); 1.8106 (0.33); 1.5813 (0.33); 1.1927 (4.46); 1.1749 (8.83);1.1571 (4.3); 0.0079 (0.33); −0.0002 (6.07) Ex. I-41, Solvent: DMSO-d₆8.7994 (0.47); 8.4174 (0.9); 8.2839 (0.36); 8.2697 (0.35); 8.0449(0.54); 8.0402 (10.68); 7.2726 (1.64); 7.2052 (0.34); 7.1838 (3.6);7.1299 (1.86); 7.1248 (0.46); 7.0951 (1.84); 7.0875 (2.13); 7.0852(2.25); 7.0747 (2.17); 7.0724 (2.24); 7.0499 (0.42); 7.0393 (4.58);7.0249 (1.31); 7.0223 (1.23); 7.0116 (2.05); 7.0103 (1.98); 6.9995(1.42); 6.9969 (1.33); 6.9488 (2.1); 6.9259 (0.47); 6.9138 (4.9); 6.6961(2.67); 6.6945 (2.7); 6.6828 (2.55); 6.6811 (2.46); 6.5725 (1.38);6.5709 (1.35); 6.5601 (2.51); 6.5586 (2.39); 6.5478 (1.31); 6.5461(1.24); 5.7809 (1.45); 5.7643 (16); 5.7492 (1.47); 5.4542 (1.24); 5.4257(2.63); 5.4082 (0.39); 5.3775 (3.26); 5.349 (1.46); 5.0277 (5.17); 4.357(0.98); 4.3351 (1.06); 3.9735 (0.97); 3.9504 (1.06); 3.8413 (1.49);3.8232 (1.73); 3.8129 (1.83); 3.7948 (1.55); 3.4055 (0.41); 3.3991(0.75); 3.3928 (0.53); 3.3862 (0.85); 3.3799 (1.46); 3.3737 (0.93);3.3672 (0.66); 3.3607 (0.98); 3.3462 (82.73); 3.3226 (1.35); 3.2793(0.79); 3.2593 (1.37); 3.2524 (2.16); 3.2375 (2.58); 3.23 (0.42); 3.2239(1.86); 3.2091 (1.7); 3.1955 (1.72); 2.8489 (0.87); 2.8292 (1.24);2.8103 (0.71); 2.6183 (0.45); 2.6153 (0.62); 2.6122 (0.45); 2.565(0.84); 2.5427 (0.34); 2.5243 (1.2); 2.5212 (1.52); 2.5181 (1.48);2.5093 (32.91); 2.5063 (73.12); 2.5032 (101.55); 2.5002 (73.05); 2.4972(32.78); 2.3902 (0.43); 2.3871 (0.59); 2.3841 (0.42); 2.1241 (0.84);2.1025 (1.06); 2.1 (1.06); 2.0869 (1.05); 2.0652 (1.02); 1.8294 (0.37);1.8156 (0.74); 1.8095 (0.84); 1.795 (0.81); 1.7891 (0.8); 1.7753 (0.41);1.7681 (0.38); 1.766 (0.39); 1.5923 (0.32); 1.5855 (0.38); 1.5717(0.78); 1.5654 (0.86); 1.5513 (0.86); 1.545 (0.85); 1.5314 (0.44);1.5244 (0.39); 1.4077 (0.38); 1.3509 (0.49); 1.2987 (1.71); 1.258(2.56); 1.234 (1.6); 0.8535 (0.36); −0.0001 (1.81) Ex. I-42, Solvent:DMSO-d₆ 9.4493 (7.94); 8.7772 (0.82); 8.4303 (0.53); 8.0283 (0.8);8.0179 (7.95); 7.308 (1.64); 7.2965 (0.35); 7.209 (0.44); 7.1937 (1.66);7.1745 (6.63); 7.1597 (2.59); 7.1549 (2.47); 7.0415 (1.86); 7.0235(4.22); 7.0145 (0.94); 6.9974 (0.37); 6.9001 (4.83); 6.8877 (2.35);6.8786 (0.55); 6.7924 (2.09); 6.7697 (3.43); 6.7634 (3.24); 6.7228(1.76); 6.721 (1.78); 6.7169 (1.49); 6.7027 (1.59); 6.7006 (1.53);6.6969 (1.39); 5.6685 (1.23); 5.649 (1.52); 5.6413 (1.44); 5.622 (1.29);5.5927 (0.65); 5.4513 (0.76); 5.409 (2.91); 5.3689 (3.36); 5.3259(0.87); 4.3621 (0.97); 4.329 (1.06); 4.0571 (1.25); 4.0393 (3.76);4.0216 (3.82); 4.0037 (1.47); 3.9832 (0.95); 3.9469 (1.09); 3.8812(1.39); 3.8537 (1.5); 3.8382 (1.7); 3.8108 (1.45); 3.4222 (0.58); 3.4129(0.84); 3.4038 (0.77); 3.3938 (1.08); 3.3846 (1.54); 3.3758 (1.09);3.3643 (0.97); 3.3557 (1.28); 3.3355 (3.2); 3.3073 (237.48); 3.2837(4.75); 3.2733 (3.42); 3.2409 (1.06); 2.874 (0.79); 2.8447 (1.37);2.8145 (0.77); 2.6694 (0.4); 2.5656 (0.51); 2.5393 (0.89); 2.5087(24.65); 2.5047 (42.64); 2.5003 (53.05); 2.4961 (36.83); 2.3314 (0.34);2.3271 (0.4); 2.3225 (0.32); 2.1358 (1.03); 2.1026 (2.05); 2.069 (1.35);1.9868 (16); 1.8419 (0.45); 1.823 (0.87); 1.8133 (0.91); 1.7906 (0.85);1.7625 (0.39); 1.6224 (0.38); 1.6116 (0.45); 1.5906 (0.87); 1.5821(0.91); 1.5603 (0.89); 1.5521 (0.84); 1.5307 (0.43); 1.3979 (0.61);1.1928 (4.39); 1.175 (8.6); 1.1572 (4.23); −0.0002 (0.79) Ex. I-43,Solvent: DMSO-d₆ 8.7778 (0.33); 8.0198 (5.88); 7.9699 (1.46); 7.967(1.51); 7.9504 (1.6); 7.9475 (1.57); 7.668 (0.58); 7.6648 (0.6); 7.6487(1.35); 7.6301 (1.08); 7.6269 (1.02); 7.573 (1.76); 7.5557 (1.09);7.4867 (0.94); 7.4835 (0.88); 7.4677 (1.45); 7.465 (1.36); 7.4491(0.72); 7.4458 (0.65); 7.3042 (1.08); 7.1709 (2.45); 7.1579 (1.29);7.0377 (1.24); 7.0219 (2.86); 6.8984 (2.52); 6.8861 (1.46); 6.3307(0.91); 6.3144 (1.04); 6.3028 (1.02); 6.2866 (0.9); 5.7471 (1.24);5.4458 (0.47); 5.403 (1.82); 5.3634 (1.83); 5.3207 (0.47); 4.3556(0.57); 4.3222 (0.64); 4.066 (1.02); 4.0384 (1.29); 4.022 (1.63); 3.9941(1.12); 3.9744 (0.58); 3.9402 (0.65); 3.896 (0.51); 3.882 (16); 3.8764(2.11); 3.4031 (0.42); 3.3947 (0.62); 3.3847 (0.54); 3.3754 (0.76);3.3659 (1.16); 3.3561 (0.96); 3.3096 (206.94); 3.2574 (0.88); 3.2373(1.34); 3.2211 (1.51); 3.1932 (1.1); 3.1771 (1.05); 2.8592 (0.39);2.8301 (0.71); 2.8006 (0.42); 2.5099 (10.14); 2.5056 (18.43); 2.5011(23.66); 2.4968 (16.39); 2.4925 (7.85); 2.1203 (0.51); 2.0857 (1.04);2.0701 (0.82); 2.0479 (0.61); 1.9873 (1.86); 1.8084 (0.45); 1.7991(0.46); 1.7779 (0.45); 1.7692 (0.4); 1.573 (0.44); 1.5639 (0.48); 1.5416(0.45); 1.5338 (0.43); 1.3978 (0.45); 1.1931 (0.5); 1.1754 (0.99);1.1576 (0.49); −0.0002 (0.69) Ex. I-44, Solvent: DMSO-d₆ 8.0475 (5.06);7.495 (1.24); 7.4826 (1.6); 7.4102 (1.83); 7.4041 (3.54); 7.3971 (0.34);7.3692 (0.83); 7.3634 (0.77); 7.3604 (0.54); 7.3566 (0.75); 7.3501(0.61); 7.342 (0.43); 7.2712 (0.78); 7.1826 (1.81); 7.1267 (0.87); 7.094(0.87); 7.0363 (2.12); 6.9459 (0.98); 6.9113 (2.22); 6.1015 (0.88);6.0881 (1); 6.083 (0.96); 6.0696 (0.87); 5.7625 (0.41); 5.453 (0.7);5.4246 (1.58); 5.3741 (1.55); 5.3457 (0.71); 4.9788 (1.52); 4.9595(2.11); 4.8775 (2.19); 4.8582 (1.56); 4.3593 (0.5); 4.3374 (0.52); 4.024(0.84); 4.0055 (0.96); 3.9953 (1.04); 3.9768 (1.33); 3.9536 (0.52);3.5692 (16); 3.405 (0.43); 3.3921 (0.47); 3.386 (0.78); 3.3797 (0.47);3.3665 (0.43); 3.3179 (0.96); 3.3045 (0.98); 3.2891 (1.01); 3.2846(0.4); 3.2758 (1.06); 3.2601 (0.69); 3.2413 (0.38); 2.9439 (4.47);2.8484 (0.35); 2.8279 (0.64); 2.8105 (0.35); 2.7838 (3.59); 2.6147(0.39); 2.5647 (2.32); 2.524 (0.48); 2.5209 (0.66); 2.5178 (0.79);2.5088 (22.38); 2.506 (47.3); 2.503 (64.84); 2.5 (47.32); 2.4972(22.18); 2.3872 (0.4); 2.1253 (0.44); 2.1059 (0.53); 2.0882 (0.49);2.0771 (0.56); 2.0671 (0.48); 1.958 (3.87); 1.9096 (0.52); 1.8112(0.39); 1.8049 (0.43); 1.7908 (0.41); 1.7849 (0.38); 1.5726 (0.4);1.5662 (0.42); 1.5519 (0.43); 1.5458 (0.4); −0.0002 (7.43) Ex. I-45,Solvent: DMSO-d₆ 9.8994 (0.63); 8.6648 (0.61); 8.0229 (16); 7.4357(1.96); 7.4324 (2.4); 7.4236 (1.91); 7.4213 (2.43); 7.3478 (1.87);7.3445 (1.38); 7.3368 (3.12); 7.3327 (3.24); 7.3236 (0.36); 7.3188(0.75); 7.3155 (1.2); 7.3066 (3.51); 7.3034 (2.83); 7.2992 (3.06);7.2958 (5.35); 7.2914 (2.5); 7.2872 (2.31); 7.2844 (1.96); 7.2752(0.76); 7.272 (0.84); 7.2686 (1.88); 7.18 (4.51); 7.1262 (2.14); 7.0915(2.15); 7.0358 (5.68); 6.9455 (2.53); 6.9112 (4.84); 5.9981 (1.98);5.985 (2.2); 5.9797 (2.14); 5.9666 (1.95); 5.4504 (1.65); 5.422 (3.66);5.3725 (3.49); 5.3442 (1.59); 5.2615 (2.95); 5.2525 (6.4); 5.2434(3.09); 4.5916 (5.58); 4.5828 (6.19); 4.3573 (1.04); 4.3356 (1.09);4.0458 (0.36); 4.0339 (1.18); 4.022 (1.16); 4.0102 (0.41); 3.9728(1.02); 3.9502 (1.11); 3.9242 (2.07); 3.9057 (2.46); 3.8955 (2.62);3.8771 (2.16); 3.4048 (0.53); 3.399 (0.98); 3.3921 (0.76); 3.3858(1.32); 3.3796 (2.18); 3.3733 (1.71); 3.3708 (1.53); 3.3455 (1366.81);3.3281 (1.18); 3.3219 (7.12); 3.2787 (0.87); 3.2676 (2.65); 3.2545(3.25); 3.2389 (3.08); 3.2259 (2.39); 2.8468 0.77); 2.8292 (1.33);2.8093 (0.77); 2.6345 (0.44); 2.6205 (0.48); 2.6175 (1.06); 2.6144(1.48); 2.6114 (1.06); 2.6083 (0.44); 2.564.5 (7.75); 2.5421 (0.9);2.5237 (2.39); 2.5207 (3.2); 2.5175 (3.58); 2.5088 (77.52); 2.5057(170.79); 2.5027 (231.96); 2.4996 (165.03); 2.4966 (71.78); 2.3929(0.47); 2.3899 (1.05); 2.3869 (1.45); 2.3838 (1.01); 2.3806 (0.47);2.1874 (0.42); 2.1221 (0.94); 2.1026 (1.13); 2.0865 (1.06); 2.0767(2.1); 2.0628 (1.01); 1.9898 (5.36); 1.9087 (0.57); 1.8306 (0.39);1.8242 (0.4); 1.811 (0.84); 1.8039 (0.89); 1.7902 (0.88); 1.7837 (0.81);1.7698 (0.36); 1.5906 (0.36); 1.5839 (0.47); 1.5703 (0.89); 1.5637(1.01); 1.5495 (0.96); 1.5436 (0.89); 1.5297 (0.41); 1.397 (2.51);1.3003 (0.45); 1.2339 (0.42); 1.186 (1.58); 1.1742 (3.29); 1.1623(1.47); −0.0002 (4.77) Ex. I-46, Solvent: DMSO-d₆ 8.0198 (0.55); 7.9687(1.48); 7.9658 (1.51); 7.9492 (1.63); 7.9462 (1.59); 7.6807 (0.58);7.6774 (0.6); 7.6615 (1.34); 7.6427 (1.06); 7.6394 (0.96); 7.5663 (1.7);7.5478 (1.16); 7.4963 (0.94); 7.4933 (0.87); 7.4773 (1.47); 7.4746(1.37); 7.4586 (0.74); 7.4555 (0.65); 7.2868 (1.01); 7.1535 (2.44);7.1487 (1.38); 7.0205 (1.47); 7.0125 (2.57); 6.8914 (2.33); 6.8765(1.25); 6.3284 (0.9); 6.3115 (1.04); 6.3002 (1.01); 6.2834 (0.89);5.7472 (1.05); 5.4238 (0.46); 5.3815 (1.75); 5.3629 (0.38); 5.3439(1.73); 5.3017 (0.44); 4.3222 (0.6); 4.2884 (0.56); 4.1332 (0.95);4.1048 (1.14); 4.0886 (1.26); 4.0603 (1.09); 4.0395 (0.55); 4.0216(0.6); 3.946 (0.59); 3.9122 (0.64); 3.8815 (2.97); 3.8756 (16); 3.364(0.67); 3.3066 (262.77); 3.2665 (1.62); 3.2497 (1.65); 3.2364 (0.45);3.2219 (1.75); 3.2053 (1.2); 3.1923 (0.49); 2.8275 (0.43); 2.7989(0.68); 2.7687 (0.36); 2.5396 (0.5); 2.5094 (17.55); 2.5052 (31.81);2.5007 (40.84); 2.4963 (28.27); 2.492 (13.58); 2.0699 (0.96); 2.0428(1.01); 2.0081 (0.55); 1.9871 (2.09); 1.7583 (0.42); 1.7513 (0.45);1.726 (0.4); 1.5359 (0.46); 1.5279 (0.46); 1.5054 (0.43); 1.4963 (0.38);1.398 (0.61); 1.1971 (0.4); 1.1931 (0.61); 1.1789 (0.84); 1.1753 (1.24);1.1575 (0.61); −0.0002 (1.5) Ex. I-47, Solvent: DMSO-d₆ 8.0201 (8.85);7.3382 (4.89); 7.3163 (5.8); 7.1785 (3.4); 7.1663 (1.65); 7.0454 (1.74);7.0304 (3.94); 6.997 (0.61); 6.99 (6.2); 6.9849 (1.95); 6.9681 (5.65);6.9068 (3.57); 6.8946 (1.86); 5.6895 (1.29); 5.6676 (1.57); 5.6625(1.56); 5.6404 (1.34); 5.4585 (0.77); 5.4161 (2.59); 5.3737 (2.58);5.3312 (0.82); 4.7544 (3.69); 4.7492 (7.22); 4.7439 (3.96); 4.3653(0.77); 4.333 (0.82); 3.9834 (0.7); 3.9527 (0.77); 3.85 (1.3); 3.8228(1.57); 3.8068 (1.82); 3.78 (1.47); 3.4279 (0.53); 3.416 (0.87); 3.3975(0.94); 3.3891 (2.92); 3.3789 (1.33); 3.3676 (2.99); 3.3445 (134.57);3.3385 (175); 3.3322 (300.5); 3.3307 (334.71); 3.2696 (1.14); 3.2393(0.64); 2.8687 (0.53); 2.8378 (0.96); 2.8109 (0.55); 2.6752 (0.67);2.6705 (0.79); 2.6661 (0.62); 2.5411 (0.49); 2.5243 (1.49); 2.506(90.88); 2.5019 (122.12); 2.3333 (0.65); 2.3287 (0.84); 2.2509 (0.5);2.2454 (1.08); 2.2402 (0.63); 2.2319 (1.53); 2.2267 (3.22); 2.2215(1.51); 2.2133 (1.6); 2.2081 (3.44); 2.2028 (1.58); 2.1945 (0.68);2.1893 (1.18); 2.1843 (0.56); 2.1395 (0.65); 2.1052 (1.39); 2.073(2.87); 1.9885 (0.63); 1.8206 (0.61); 1.8124 (0.65); 1.7915 (0.6);1.7816 (0.6); 1.589 (0.61); 1.5782 (0.73); 1.5562 (0.62); 1.5494 (0.63);1.2354 (0.59); 1.1745 (0.37); 1.0686 (7.63); 1.05 (16); 1.0312 (7.23);−0.0002 (6.53) Ex. I-48, Solvent: DMSO-d₆ 16.1708 (0.4); 14.1949 (0.4);8.0206 (11.08); 7.338 (5.82); 7.3163 (6.87); 7.179 (4.05); 7.1667(2.13); 7.0617 (0.39); 7.0457 (2.11); 7.0308 (4.58); 6.9876 (7.25);6.9657 (6.39); 6.9072 (4.18); 6.8949 (2.24); 5.689 (1.51); 5.6685(1.95); 5.6626 (1.9); 5.6414 (1.54); 5.4595 (1.02); 5.4162 (3.18);5.3737 (3.01); 5.332 (0.97); 4.7412 (6.34); 4.7355 (6.31); 4.3661(1.06); 4.3351 (1.05); 3.9863 (1.05); 3.9515 (1.06); 3.8497 (1.47);3.823 (1.89); 3.8067 (2.08); 3.7799 (1.76); 3.7105 (0.49); 3.5114(0.41); 3.4946 (0.43); 3.4615 (0.44); 3.4534 (0.43); 3.4442 (0.43);3.4258 (0.72); 3.4162 (1.25); 3.3984 (1.64); 3.3899 (3.87); 3.3679(4.4); 3.3449 (249.75); 3.3367 (240.68); 3.3323 (386.08); 3.3309(361.35); 3.27 (1.58); 3.2389 (0.98); 3.2014 (0.41); 2.8672 (0.79);2.8447 (1.24); 2.8112 (0.76); 2.6749 (0.79); 2.6706 (1.02); 2.5411(0.71); 2.502 (150.05); 2.4522 (0.46); 2.3283 (1.08); 2.1327 (0.91);2.1207 (0.73); 2.1032 (1.79); 2.0824 (0.86); 2.0731 (5.8); 1.8308(7.32); 1.825 (16); 1.8192 (7.93); 1.7909 (0.87); 1.7561 (0.44); 1.6181(0.52); 1.6114 (0.44); 1.5873 (0.95); 1.5788 (0.88); 1.5577 (0.82);1.5486 (0.91); 1.5296 (0.4); 1.3503 (0.49); 1.235 (1.1); −0.0002 (10.3);−0.0086 (0.6) Ex. I-49, Solvent: DMSO-d₆ 11.229 (0.54); 7.966 (16);7.4173 (2.95); 7.3966 (4.92); 7.3761 (4.16); 7.3179 (2.23); 7.1847(5.22); 7.1669 (4.74); 7.1615 (5.88); 7.1453 (3.62); 7.1416 (4.91);7.0517 (2.56); 7.0355 (6.07); 6.915 (4.71); 6.8997 (2.8); 6.2406 (2.1);6.2163 (2.68); 6.2101 (2.45); 6.1853 (2.05); 5.7564 (15.94); 5.465(1.16); 5.4225 (3.63); 5.3806 (3.49); 5.3384 (1.02); 4.8414 (0.53);4.8347 (0.44); 4.8008 (4.39); 4.7923 (5.49); 4.7861 (4.32); 4.7524(0.41); 4.7463 (0.7); 4.3743 (1.09); 4.3494 (0.99); 4.3439 (1.12);4.3259 (0.33); 4.0615 (0.36); 4.0438 (0.77); 4.0262 (0.84); 3.9972 (1);3.962 (1.2); 3.94 (0.32); 3.7713 (1.63); 3.7403 (1.93); 3.7292 (2.67);3.6985 (2.21); 3.6491 (0.37); 3.6262 (0.36); 3.5878 (2.63); 3.5632(2.64); 3.5457 (1.97); 3.5213 (1.92); 3.4969 (0.85); 3.4939 (0.8);3.4682 (0.64); 3.4604 (0.9); 3.4441 (4.22); 3.4381 (8.78); 3.432 (4.65);3.4194 (2.93); 3.4063 (5.77); 3.3984 (9.03); 3.3738 (6048.35); 3.3513(14.05); 3.3368 (2.07); 3.3303 (1.971; 3.3266 (1.93); 3.3129 (2.2);3.3005 (0.77); 3.2958 (0.91); 3.2834 (1.83); 3.2569 (0.7); 3.2521(0.65); 3.2462 (0.81); 3.211 (0.37); 3.1698 (0.33); 3.0422 (0.5); 2.8868(0.73); 2.8551 (1.62); 2.827 (0.71); 2.6837 (1.2); 2.6792 (1.71); 2.6745(1.24); 2.5491 (0.92); 2.5323 (2.93); 2.5141 (178.87); 2.51 (245.29);2.5065 (161.43); 2.3413 (1.23); 2.3367 (1.66); 2.3319 (1.19); 2.1629(0.95); 2.1277 (1.77); 2.1053 (0.73); 2.0879 (1.15); 2.0777 (8.97);2.064 (0.33); 1.9944 (3.02); 1.8555 (0.4); 1.8254 (0.94); 1.8012 (0.74);1.7724 (0.36); 1.7665 (0.4); 1.6364 (0.44); 1.6299 (0.44); 1.6067(0.88); 1.5972 (0.86); 1.5749 (0.87); 1.5455 (0.39); 1.5364 (0.32);1.2404 (1.04); 1.1983 (0.95); 1.1806 (1.86); 1.1628 (0.91) Ex. I-50,Solvent: DMSO-d₆ 7.9628 (8.19); 7.3715 (1.63); 7.3509 (3.36); 7.3303(2.22); 7.3138 (1.26); 7.1805 (2.8); 7.1668 (1.22); 7.0973 (2.07);7.0951 (2.69); 7.0771 (3.29); 7.0747 (2.48); 7.059 (1.6); 7.0475 (1.37);7.0307 (3.32); 6.906 (2.65); 6.8947 (1.57); 6.2186 (1.05); 6.1935 (1.5);6.188 (1.16); 6.1631 (1.07); 5.4691 (0.61); 5.4256 (1.83); 5.3719(1.71); 5.3299 (0.68); 4.3718 (0.59); 4.3368 (0.61); 4.0802 (1.56);4.0687 (2.85); 4.0561 (2.58); 4.0379 (3.55); 4.02 (3.62); 4.002 (1.46);3.9563 (0.55); 3.7289 (0.61); 3.6982 (0.69); 3.6875 (1.65); 3.6572(1.48); 3.6468 (1.72); 3.6219 (1.72); 3.6049 (0.64); 3.5803 (0.62);3.4316 (0.52); 3.4211 (0.54); 3.4035 (2.04); 3.394 (2.91); 3.3859(2.57); 3.3741 (1.78); 3.3248 (939.63); 3.3013 (2.75); 3.2753 (0.86);3.2465 (0.57); 3.2427 (0.52); 2.8975 (14.63); 2.8755 (0.52); 2.845(0.8); 2.818 (0.48); 2.6892 (0.51); 2.6752 (0.85); 2.6703 (1.23); 2.6658(0.89); 2.661 (0.49); 2.5406 (0.8); 2.5238 (2.07); 2.519 (2.95); 2.5095(70.63); 2.5056 (125.01); 2.5014 (171.49); 2.4977 (112.07); 2.3327(0.87); 2.3282 (1.15); 2.3235 (0.88); 2.1441 (0.52); 2.1087 (0.94);2.0734 (1.28); 1.9883 (16); 1.8217 (0.51); 1.7923 (0.51); 1.5881 (0.51);1.5784 (0.49); 1.553 (0.47); 1.3982 (0.39); 1.2354 (0.63); 1.1922(4.44); 1.1744 (8.98); 1.1566 (4.44); 0.008 (1.76); −0.0002 (62.49);−0.0085 (1.59) Ex. I-51, Solvent: DMSO-d₆ 18.3412 (0.34); 16.7383(0.35); 11.2347 (0.37); 7.9496 (16); 7.3773 (3.08); 7.3568 (6.3); 7.3362(4.28); 7.316 (2.07); 7.1829 (5.12); 7.1688 (2.45); 7.1095 (3.66);7.1073 (5.16); 7.0892 (7.26); 7.0871 (7.11); 7.0678 (3.07); 7.0497(2.44); 7.0328 (6.11); 6.914 (4.66); 6.897 (2.75); 6.2663 (1.9); 6.2426(2.59); 6.2352 (2.3); 6.2115 (2.14); 5.8335 (0.54); 5.8191 (1.11);5.8067 (1.1); 5.7929 (1.49); 5.7761 (1.48); 5.7632 (1.26); 5.7525(9.43); 5.7367 (0.81); 5.4692 (1.2); 5.4258 (3.44); 5.3759 (3.36);5.3345 (1.1); 5.3208 (0.38); 5.2722 (2.98); 5.2681 (2.86); 5.2289(2.45); 5.2249 (2.31); 5.2027 (0.33); 5.0209 (2.38); 5.0174 (2.36);4.9948 (2.27); 4.991 (2.11); 4.5849 (0.71); 4.5724 (0.67); 4.5534(2.13); 4.5398 (2.08); 4.5254 (2.05); 4.5114 (2.11); 4.4939 (0.74);4.4799 (0.81); 4.3733 (1.01); 4.3387 (1.08); 4.0427 (0.45); 4.025(0.51); 4.0042 (0.66); 3.9904 (0.91); 3.9604 (1.08); 3.7645 (1.44);3.7334 (1.98); 3.7227 (2.79); 3.6918 (2.14); 3.6016 (0.34); 3.5818(2.4); 3.5584 (2.31); 3.5402 (1.84); 3.5238 (0.68); 3.5166 (1.92);3.4894 (0.61); 3.4847 (0.6); 3.4676 (0.7); 3.4573 (1.65); 3.451 (1.02);3.4347 (2.84); 3.4252 (4.94); 3.4185 (6.74); 3.3951 (4801.39); 3.3751(10.98); 3.3728 (10.61); 3.3624 (3.24); 3.3589 (3.53); 3.3523 (1.67);3.3463 (1.79); 3.336 (1.28); 3.3269 (1.53); 3.3207 (1.35); 3.3148 (1.9);3.3068 (0.92); 3.3036 (0.71); 3.2846 (1.77); 3.2573 (0.92); 3.2337(0.34); 3.2137 (0.38); 3.1704 (0.36); 3.1667 (0.4); 2.8926 (0.66);2.8576 (1.27); 2.8278 (0.72); 2.6837 (0.67); 2.6789 (0.93); 2.6745(0.77); 2.5482 (0.41); 2.5324 (1.54); 2.5141 (95.3); 2.5099 (131.13);2.5066 (86.18); 2.3416 (0.66); 2.3366 (0.9); 2.3277 (0.42); 2.1521(0.97); 2.1182 (1.79); 2.0754 (6.83); 1.9929 (1.72); 1.8512 (0.48);1.8218 (0.92); 1.8002 (0.9); 1.7666 (0.4); 1.6333 (0.5); 1.6214 (0.42);1.6023 (0.87); 1.5911 (0.87); 1.5705 (0.88); 1.5304 (0.39); 1.2393(0.73); 1.197 (0.5); 1.1792 (1.04); 1.1612 (0.48) Ex. I-52, Solvent:CD₃CN 7.7021 (16); 7.4902 (4.15); 7.4886 (4.26); 7.4772 (5.81); 7.4758(5.79); 7.4465 (4.28); 7.4446 (4.55); 7.434 (5.64); 7.4321 (6.12);7.4177 (2.57); 7.4156 (2.55); 7.4053 (5.48); 7.4031 (4.76); 7.3926(3.16); 7.3904 (2.61); 7.3628 (4.04); 7.3606 (4.01); 7.3504 (5.48);7.3481 (5.25); 7.3379 (2.08); 7.3357 (1.97); 6.9894 (4.29); 6.8994(8.98); 6.878 (4.59); 6.8321 (8.64); 6.8094 (4.5); 6.7868 (9.78); 6.6957(4.81); 6.0769 (3.71); 6.0626 (4.14); 6.0584 (4.1); 6.0441 (3.79);5.2659 (2.73); 5.2377 (8.2); 5.203 (8.19); 5.1747 (2.82); 4.8399 (6.89);4.8202 (10.83); 4.7567 (11.1); 4.737 (7.03); 4.4764 (1.97); 4.454(2.03); 3.9819 (3.93); 3.9633 (4.06); 3.9533 (4.5); 3.9347 (4.24);3.9091 (1.9); 3.8858 (2.04); 3.3625 (0.82); 3.3561 (1.71); 3.3489(5.54); 3.3434 (2); 3.3347 (5.88); 3.3307 (2.11); 3.3239 (1.36); 3.3202(4.98); 3.3112 (1.1); 3.306 (4.54); 3.2997 (1.62); 3.2952 (1.73); 3.279(2.1); 3.2756 (2.78); 3.2563 (1.64); 3.2518 (1.47); 2.867 (1.34); 2.8625(1.49); 2.8452 (2.48); 2.8418 (2.54); 2.8244 (1.52); 2.82 (1.41); 2.1905(1.72); 2.1691 (18.57); 2.1374 (1.79); 2.1164 (1.9); 1.9653 (7.38);1.9572 (0.58); 1.953 (0.79); 1.9493 (7.87); 1.9452 (14.91); 1.9411(21.83); 1.937 (14.88); 1.9328 (7.49); 1.878 (0.74); 1.8711 (0.82);1.8577 (1.71); 1.851 (1.8); 1.8366 (1.66); 1.8302 (1.68); 1.8166 (0.7);1.8096 (0.61); 1.7099 (0.79); 1.7028 (0.88); 1.6896 (1.79); 1.6828(1.87); 1.6685 (1.76); 1.6618 (1.7); 1.6485 (0.77); 1.6414 (0.69);−0.0001 (5.97)

The intensity of the sharp signals correlates to the height of thesignals in a printed example of an NMR spectrum in cm, and shows thetrue ratios of the signal intensities. In the case of broad signals,several peaks or the middle of the signal and the relative intensitythereof may be shown in comparison to the most intense signal in thespectrum.

The lists of 1H NMR peaks are similar to the conventional 1H NMRprintouts, and therefore usually contain all peaks listed in aconventional NMR interpretation.

In addition, like conventional 1H NMR printouts, they can show solventsignals, signals for stereoisomers of the target compounds, whichlikewise form part of the subject-matter of the invention, and/or peaksfor impurities.

In the reporting of compound signals in the delta range of solventsand/or water, the usual solvent peaks are in our lists of 1H NMR peaks.

USE EXAMPLES Example A Phytophthora Test (Tomato)/Protective

Solvent: 24.5 parts by weight of acetone

-   -   24.5 parts by weight of dimethylacetamide

Emulsifier: 1 part by weight of alkylaryl polyglycol ether

To prepare an appropriate active ingredient preparation, 1 part byweight of active ingredient is mixed with the stated amounts of solventand emulsifier, and the concentrate is diluted with water to the desiredconcentration.

To test for protective efficacy, young plants are sprayed with theactive ingredient preparation at the stated application rate. After thespray coating has dried on, the plants are inoculated with an aqueousspore suspension of Phytophthora infestans. The plants are then placedin an incubation cabinet at approx. 20° C., and 100% relative airhumidity.

Evaluation follows 3 days after the inoculation. 0% means an efficacywhich corresponds to that of the control, whereas an efficacy of 100%means that no infection is observed.

In this test, the following inventive compounds exhibit an efficacy of70% or more at an active ingredient concentration of 10 ppm: I-1 (95%),I-2 (99%), I-3 (100%), I-5 (93%), I-6 (94%), I-7 (97%), I-8 (97%), I-9(96%), I-10 (97%), I-14 (98%), I-15 (95%), I-19 (96%), I-20 (95%), I-21(98%), I-22 (98%), I-23 (97%), I-25 (95%), I-26 (97%), I-35 (88%), I-39(99%), I-40 (95%), I-41 (94%), I-42 (94%).

Example B Plasmopara Test (Grapevine)/Protective

Solvent: 24.5 parts by weight of acetone

-   -   24.5 parts by weight of dimethylacetamide

Emulsifier: 1 part by weight of alkylaryl polyglycol ether

To prepare an appropriate active ingredient preparation, 1 part byweight of active ingredient is mixed with the stated amounts of solventand emulsifier, and the concentrate is diluted with water to the desiredconcentration.

To test for protective efficacy, young plants are sprayed with theactive ingredient preparation at the stated application rate. After thespray coating has dried on, the plants are inoculated with an aqueousspore suspension of Plasmopara viticola and then remain in an incubationcabinet at about 20° C., and 100% relative atmospheric humidity for 1day. The plants are then placed in a greenhouse at approx. 21° C., andapprox. 90% air humidity for 4 days. The plants are then moistened andplaced in an incubation cabinet for 1 day.

Evaluation follows 6 days after the inoculation. 0% means an efficacywhich corresponds to that of the control, whereas an efficacy of 100%means that no infection is observed.

In this test, the following inventive compounds exhibit an efficacy of70% or more at an active ingredient concentration of 10 ppm: I-1 (100%),I-2 (100%), I-3 (100%), I-4 (100%), I-5 (97%), I-6 (100%), I-7 (100%),I-8 (99%), I-9 (99%), I-10 (100%), I-14 (100%), I-15 (93%), I-19 (96%),I-20 (98%), I-21 (100%), I-22 (97%), I-23 (99%), I-25 (74%), I-26(100%), I-39 (99%), I-40 (91%), I-41 (100%), I-42 (97%).

Example C Peronospora Test (Rapeseed)/Seed Treatment

The test was carried out under greenhouse conditions.

To produce an active ingredient preparation, the active ingredient wasdissolved in N-methyl-2-pyrrolidone and the concentrate was diluted withwater to the desired concentration. The rapeseeds treated with thissolution were sown in 6*6 cm pots which had been filled to a height of 4cm with a 1:1 mixture of steam-treated soil and sand. Then the plantswere cultivated at 10° C.

After 14 days, the plants were inoculated with an aqueous sporesuspension of Peronospora brassicae. Subsequently, the plants wereplaced in a greenhouse at approx. 15° C., and 100% air humidity for 7days.

The evaluation was effected by assessing the infected leaf area perplant. 0% means an efficiency which corresponds to that of the control,while an efficiency of 100% means that no infestation is observed.

In this test, the following inventive compounds at an active ingredientconcentration of 50 g/dt exhibited an efficiency of 80% or more: I-1(100%), I-6 (100%), I-7 (100%).

1-13. (canceled)
 14. A compound of formula (VIII)

wherein W¹ is acetyl, C₁-C₄-alkoxycarbonyl, benzyl, benzyloxycarbonyl or[3,5 bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl, and R¹ is hydrogen orhalogen.
 15. The compound of claim 14, wherein the R¹ is hydrogen. 16.The compound of claim 14, wherein the R¹ is halogen.
 17. The compound ofclaim 15, wherein the W¹ is [3,5bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl.
 18. The compound of claim15, wherein the W¹ is acetyl, C₁-C₄-alkoxycarbonyl, benzyl, orbenzyloxycarbonyl.
 19. The compound of claim 16, wherein the W¹ is [3,5bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl.
 20. The compound of claim16, wherein the W¹ is acetyl, C₁-C₄-alkoxycarbonyl, benzyl, orbenzyloxycarbonyl.
 21. A mixture comprising a compound of formula (VI)

and hydroxylamine, wherein W¹ is acetyl, C₁-C₄-alkoxycarbonyl, benzyl,benzyloxycarbonyl or [3,5 bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl,and R¹ is hydrogen or halogen.
 22. The mixture of claim 21, wherein theR¹ of the compound is hydrogen and the W¹ of the compound is [3,5bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl.
 23. The mixture of claim 21,wherein the R¹ of the compound is halogen and the W¹ of the compound is[3,5 bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl.